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Circulating MicroRNA in Digestive Tract Cancers

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For many decades, cell-free nucleic acids have been known to be present in peripheral blood. Several studies have identified tumor-specific and/or tumor-associated alterations in the circulating nucleic acids of patients with various cancers. In recent years, cell-free microRNA (miRNA) have been stably detected in the plasma and serum, like other molecules; their presence in the blood has attracted the attention of researchers due to their potential use as valuable blood biomarkers.1Schwarzenbach H. Hoon D.S. Pantel K. Cell-free nucleic acids as biomarkers in cancer patients.Nat Rev Cancer. 2011; 11: 426-437Crossref PubMed Scopus (2199) Google Scholar MiRNAs are short, noncoding RNAs that play important roles in various physiologic and developmental processes. The mature miRNAs are produced from long primary transcripts through 2 sequential cleavage steps. The long primary miRNA transcript is cleaved by the Drosha complex in the nucleus, generating intermediate precursor miRNA. Precursor miRNA is transported by exportin-5 from the nucleus into the cytoplasm, and then subjected to further cleavage by a Dicer RNAase III enzyme, generating a short double-strand miRNA. One strand (guided strand) of mature miRNA is then incorporated into the RNA-induced silencing complex and subsequently hybridize to the 3′-untranslated region of their target mRNAs to repress translation or degrade these mRNAs. Thus, a single miRNA can influence the expression of hundreds of genes and allow them to function in a coordinated manner. Therefore, miRNAs have been implicated as key molecules in all cellular processes. Numerous studies have shown that alterations in miRNA expression correlate with various diseases, including the development and progression of cancer, and some miRNAs can function as oncogenes or tumor suppressors. These findings have opened up a new and interesting field in the diagnosis of cancer and the treatments of cancer patients. Mitchell et al2Mitchell P.S. Parkin R.K. Kroh E.M. et al.Circulating microRNAs as stable blood-based markers for cancer detection.Proc Natl Acad Sci U S A. 2008; 105: 10513-10518Crossref PubMed Scopus (6792) Google Scholar first demonstrated that circulating miRNAs had the potential to be new biomarkers in patients with solid cancers. In recent years, several papers have demonstrated that circulating miRNAs can also be detected in the peripheral blood of patients with digestive tract cancers. Although the origins and physiologic functions of cell-free miRNAs in the blood remain to be fully elucidated, a noninvasive assay for miRNAs should be developed to exploit these molecules as potential diagnostic and prognostic biomarkers. This assay undoubtedly contributes to an improvement in the clinical outcomes of cancer patients. In this article, we review the current state of biological and clinical research regarding circulating miRNAs of digestive tract cancer patients and discuss the future perspectives. It has been theorized that the necrosis and the apoptosis of tumor cells are the main sources of cell-free nucleic acids in the plasma and serum. However, several recent studies have demonstrated that extracellular nucleic acids, especially miRNAs, occur not only through cell lysis but also through active secretion.1Schwarzenbach H. Hoon D.S. Pantel K. Cell-free nucleic acids as biomarkers in cancer patients.Nat Rev Cancer. 2011; 11: 426-437Crossref PubMed Scopus (2199) Google Scholar, 3Valadi H. Ekström K. Bossios A. et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat Cell Biol. 2007; 9: 654-659Crossref PubMed Scopus (9739) Google Scholar, 4Kosaka N. Iguchi H. Yoshioka Y. et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells.J Biol Chem. 2010; 285: 17442-17452Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar, 5Pigati L. Yaddanapudi S.C. Iyengar R. et al.Selective release of microRNA species from normal and malignant mammary epithelial cells.PLoS One. 2010; 5: e13515Crossref PubMed Scopus (497) Google Scholar Cell-derived endogenous miRNAs are present in the blood in a remarkably stable form that is protected from endogenous RNase activity. In contrast, synthetic exogenous miRNAs are rapidly degraded when added directly to the plasma.2Mitchell P.S. Parkin R.K. Kroh E.M. et al.Circulating microRNAs as stable blood-based markers for cancer detection.Proc Natl Acad Sci U S A. 2008; 105: 10513-10518Crossref PubMed Scopus (6792) Google Scholar Kosaka et al4Kosaka N. Iguchi H. Yoshioka Y. et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells.J Biol Chem. 2010; 285: 17442-17452Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar clearly demonstrated that a subset of miRNAs was packaged into exosome vesicles and released through a ceramide-dependent secretory mechanism. Arroyo et al6Arroyo J.D. Chevillet J.R. Kroh E.M. et al.Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma.Proc Natl Acad Sci U S A. 2011; 108: 5003-5008Crossref PubMed Scopus (2672) Google Scholar systematically investigated circulating miRNAs in the plasma and serum using differential centrifugation and size-exclusion chromatography techniques. This group demonstrated ≥2 populations of circulating miRNAs in the plasma and serum and discovered agonaute-2, a key effector protein involved in miRNA-mediated silencing as an miRNA carrier in the blood.6Arroyo J.D. Chevillet J.R. Kroh E.M. et al.Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma.Proc Natl Acad Sci U S A. 2011; 108: 5003-5008Crossref PubMed Scopus (2672) Google Scholar In addition, high-density lipoprotein has been described as an alternative transporter of extracellular miRNAs in human plasma.7Vickers K.C. Palmisano B.T. Shoucri B.M. et al.MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins.Nat Cell Biol. 2011; 13: 423-433Crossref PubMed Scopus (2256) Google Scholar All circulating miRNAs, regardless of whether they are incorporated into protein complexes and/or cell-derived microvesicles, seem to be adequately protected against the degradation caused by the abundant RNases in human plasma and serum. Indeed, the extracellular miRNAs in the plasma and serum are extremely stable under severe conditions, such as extended storage and exposure to multiple freeze–thaw cycles.2Mitchell P.S. Parkin R.K. Kroh E.M. et al.Circulating microRNAs as stable blood-based markers for cancer detection.Proc Natl Acad Sci U S A. 2008; 105: 10513-10518Crossref PubMed Scopus (6792) Google Scholar Regarding the composition of circulating miRNAs, Pigati et al5Pigati L. Yaddanapudi S.C. Iyengar R. et al.Selective release of microRNA species from normal and malignant mammary epithelial cells.PLoS One. 2010; 5: e13515Crossref PubMed Scopus (497) Google Scholar investigated the difference between extracellular and cellular miRNAs using epithelial cell lines and concluded that the release of miRNAs did not necessarily reflect the abundance of miRNAs in the cell of origin. Kosaka et al4Kosaka N. Iguchi H. Yoshioka Y. et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells.J Biol Chem. 2010; 285: 17442-17452Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar also demonstrated that some specific miRNAs were expressed to a greater extent in cell-derived exosomes compared with their donor cells.4Kosaka N. Iguchi H. Yoshioka Y. et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells.J Biol Chem. 2010; 285: 17442-17452Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar Moreover, other groups demonstrated that the non–vesicle-associated miRNA profiles within protein complexes were distinctly different from the purified, exosomes-associated miRNA profiles.6Arroyo J.D. Chevillet J.R. Kroh E.M. et al.Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma.Proc Natl Acad Sci U S A. 2011; 108: 5003-5008Crossref PubMed Scopus (2672) Google Scholar These findings indicate that intracellular miRNAs are exported to the extracellular environment through a selective secretion mechanism. Interestingly, recent studies have demonstrated that extracellular miRNAs not only circulate in stable forms, but can also be incorporated into other surrounding and distant recipient cells in which they fulfill distinctive functions.8Skog J. Würdinger T. van Rijn S. et al.Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers.Nat Cell Biol. 2008; 10: 1470-1476Crossref PubMed Scopus (3954) Google Scholar, 9Rechavi O. Erlich Y. Amram H. et al.Cell contact–dependent acquisition of cellular and viral nonautonomously encoded small RNAs.Genes Dev. 2009; 23: 1971-1979Crossref PubMed Scopus (100) Google Scholar, 10Zernecke A. Bidzhekov K. Noels H. et al.Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection.Sci Signal. 2009; 2: ra81Crossref PubMed Scopus (1130) Google Scholar, 11Kosaka N. Iguchi H. Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis.Cancer Sci. 2010; 101: 2087-2092Crossref PubMed Scopus (1144) Google Scholar, 12Pegtel D.M. Cosmopoulos K. Thorley–Lawson D.A. et al.Functional delivery of viral miRNAs via exosomes.Proc Natl Acad Sci U S A. 2010; 107: 6328-6333Crossref PubMed Scopus (1309) Google Scholar, 13Kosaka N. Iguchi H. Yoshioka Y. et al.Competitive Interactions of Cancer Cells and Normal Cells via Secretory MicroRNAs.J Biol Chem. 2012; 287: 1397-1405Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar Rechavi et al9Rechavi O. Erlich Y. Amram H. et al.Cell contact–dependent acquisition of cellular and viral nonautonomously encoded small RNAs.Genes Dev. 2009; 23: 1971-1979Crossref PubMed Scopus (100) Google Scholar demonstrated that functional signals spread across cell boundaries between immune cells in a contact-dependent manner. Pegtel et al12Pegtel D.M. Cosmopoulos K. Thorley–Lawson D.A. et al.Functional delivery of viral miRNAs via exosomes.Proc Natl Acad Sci U S A. 2010; 107: 6328-6333Crossref PubMed Scopus (1309) Google Scholar reported that Epstein–Barr virus miRNAs were secreted from infected B cells and were present in both the circulation and noninfected non-B cells. This group also demonstrated that miRNAs were transferred from infected to noninfected cells in vivo and were functional (upon transfer via exosomes) in primary monocyte-derived dendritic cells. Other groups have shown that miR-126 in apoptotic bodies derived from atherosclerotic endothelial cells induces the CXCL-12–dependent vascular protection process in recipient vascular cells.10Zernecke A. Bidzhekov K. Noels H. et al.Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection.Sci Signal. 2009; 2: ra81Crossref PubMed Scopus (1130) Google Scholar There have also been some reports regarding miRNA-mediated intercellular communication in a neoplastic environment. Skog et al8Skog J. Würdinger T. van Rijn S. et al.Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers.Nat Cell Biol. 2008; 10: 1470-1476Crossref PubMed Scopus (3954) Google Scholar reported that microvesicles that housed miRNAs derived from glioblastomas were taken up by and fulfilled functions in human brain microvascular endothelial cells in culture. Kosaka et al4Kosaka N. Iguchi H. Yoshioka Y. et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells.J Biol Chem. 2010; 285: 17442-17452Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar also demonstrated that miR-146a, which is a tumor-suppressive miRNA in prostate cancer, significantly knocked down the target ROCK1 protein expression and decreased cell proliferation in a recipient prostate cancer cell line.4Kosaka N. Iguchi H. Yoshioka Y. et al.Secretory mechanisms and intercellular transfer of microRNAs in living cells.J Biol Chem. 2010; 285: 17442-17452Abstract Full Text Full Text PDF PubMed Scopus (1591) Google Scholar Their subsequent paper demonstrated that a variety of tumor-suppressive miRNAs were secreted by a normal adult prostatic epithelial cell line, and among these secretory miRNAs, miR-143 could inhibit growth exclusively in cancer cells both in vitro and in vivo.13Kosaka N. Iguchi H. Yoshioka Y. et al.Competitive Interactions of Cancer Cells and Normal Cells via Secretory MicroRNAs.J Biol Chem. 2012; 287: 1397-1405Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar Other groups found that the let-7 miRNA family was abundant in the extracellular fractions derived from a metastatic gastric cancer (GC) cell line, but not those derived from a low metastatic parental cell line, and it has been speculated that some cancer cells maintain their oncogenesis via specific extracellular miRNAs.14Ohshima K. Inoue K. Fujiwara A. et al.Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line.PLoS One. 2010; 5: e13247Crossref PubMed Scopus (515) Google Scholar On the other hand, exosomes released from neoplastic cells have been reported to suppress immune surveillance, and cell-free miRNAs contained within the exosomes may be responsible for the immunosuppression systems.15Zhang H.G. Grizzle W.E. Exosomes and cancer: a newly described pathway of immune suppression.Clin Cancer Res. 2011; 17: 959-964Crossref PubMed Scopus (233) Google Scholar These findings support the presence of miRNA-mediated intercellular communication in the normal cellular environment and the tumor environment (Figure 1) . Several methods can be used for extracting miRNAs; however, efficient protocols with high reproducibility should be utilized for the extraction of circulating miRNAs owing to the small amounts present in the plasma and serum. Commercial extraction kits that utilize glass fiber filters in the purification process have been widely used for clinical blood samples, and there are several methods for quantification. A polymerase chain reaction (PCR)-based technique using a stem-loop reverse-transcriptase (RT) primer has been widely used for determining quantity. A microarray assay, which can analyze hundreds of miRNAs simultaneously, has also been utilized for the identification of a specific marker among many circulating miRNAs. Recent advances in technology allow for the use of an oligonucleotide array to quantify the amount of circulating miRNAs without the need for PCR. Most recently, researchers have identified circulating miRNAs as new diagnostic markers in patients with cancer using direct sequencing methods16Brase J.C. Wuttig D. Kuner R. et al.Serum microRNAs as non–invasive biomarkers for cancer.Mol Cancer. 2010; 9: 306Crossref PubMed Scopus (366) Google Scholar (Table 117Zhang C. Wang C. Chen X. et al.Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma.Clin Chem. 2010; 56: 1871-1879Crossref PubMed Scopus (289) Google Scholar, 18Komatsu S. Ichikawa D. Takeshita H. et al.Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma.Br J Cancer. 2011; 105: 104-111Crossref PubMed Scopus (233) Google Scholar, 19Tsujiura M. Ichikawa D. Komatsu S. et al.Circulating microRNAs in plasma of patients with gastric cancers.Br J Cancer. 2010; 102: 1174-1179Crossref PubMed Scopus (578) Google Scholar, 20Liu R. Zhang C. Hu Z. et al.A five-microRNA signature identified from genome–wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis.Eur J Cancer. 2011; 47: 784-791Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 21Liu H. Zhu L. Liu B. et al.Genome-wide microRNA profiles identify miR-–378 as a serum biomarker for early detection of gastric cancer.Cancer Lett. 2012; 316: 196-203Crossref PubMed Scopus (234) Google Scholar, 22Konishi H. Ichikawa D. Komatsu S. et al.Detection of gastric cancer–associated microRNAs on microRNA microarray comparing pre- and post-operative plasma.Br J Cancer. 2012; 106: 740-747Crossref PubMed Scopus (165) Google Scholar, 23Ng E.K. Chong W.W. Jin H. et al.Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening.Gut. 2009; 58: 1375-1381Crossref PubMed Scopus (1055) Google Scholar, 24Huang Z. Huang D. Ni S. et al.Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer.Int J Cancer. 2010; 127: 118-126Crossref PubMed Scopus (868) Google Scholar, 25Wang L.G. Gu J. Serum is a promising novel marker for early detection of colorectal 2012; PubMed Scopus Google Scholar, H. Zhang L. et al.Circulating plasma is a novel biomarker for metastatic cancer and One. 2011; PubMed Scopus Google Scholar, Huang et al.Circulating directly from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is with 2010; PubMed Scopus Google Scholar, Y. Kosaka N. M. et as a potential diagnostic marker for 2009; PubMed Scopus Google Scholar, Zhang K. H. et al.Circulating microRNAs as biomarkers for 2011; PubMed Scopus Google Scholar, Wang H. et al.Serum as for in with B One. 2011; PubMed Scopus Google Scholar, J. C. X. et al.Circulating and in patients with or 2011; PubMed Scopus Google Scholar, J. L. X. Hu J. et al.Plasma to 2011; PubMed Scopus Google Scholar, Y. H. H. et al.Circulating as a novel biomarker for 2012; 56: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. X. et al.Serum microRNA as a potential marker for Sci. 2011; PubMed Scopus Google Scholar, J. Chen J. et al.MicroRNAs in plasma of patients as novel blood-based biomarkers of Res. 2009; 2: PubMed Scopus Google Scholar, A. N. et and and in with circulating and Res. 2010; PubMed Scopus Google Scholar, Huang X. H. et al.Circulating as a novel marker in 2010; PubMed Scopus Google Scholar, S. K. Chen et expressed miRNAs in the plasma may provide a signature for J Res. 2010; Google Scholar, N. A. et and serum microRNAs in the and in patients with One. 2011; PubMed Scopus Google Scholar, R. Komatsu S. Ichikawa D. et diagnostic of circulating in plasma of patients with J Cancer. 2011; 105: PubMed Scopus Google Scholar, J. J. Y. et of plasma microRNAs with serum for early detection of cancer.Int J Cancer. 2011; Scopus Google miRNAs in cell or other C. Wang C. Chen X. et al.Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma.Clin Chem. 2010; 56: 1871-1879Crossref PubMed Scopus (289) Google S. Ichikawa D. Takeshita H. et al.Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma.Br J Cancer. 2011; 105: 104-111Crossref PubMed Scopus (233) Google M. Ichikawa D. Komatsu S. et al.Circulating microRNAs in plasma of patients with gastric cancers.Br J Cancer. 2010; 102: 1174-1179Crossref PubMed Scopus (578) Google or other R. Zhang C. Hu Z. et al.A five-microRNA signature identified from genome–wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis.Eur J Cancer. 2011; 47: 784-791Abstract Full Text Full Text PDF PubMed Scopus (392) Google in the H. Zhu L. Liu B. et al.Genome-wide microRNA profiles identify miR-–378 as a serum biomarker for early detection of gastric cancer.Cancer Lett. 2012; 316: 196-203Crossref PubMed Scopus (234) Google H. Ichikawa D. Komatsu S. et al.Detection of gastric cancer–associated microRNAs on microRNA microarray comparing pre- and post-operative plasma.Br J Cancer. 2012; 106: 740-747Crossref PubMed Scopus (165) Google E.K. Chong W.W. Jin H. et al.Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening.Gut. 2009; 58: 1375-1381Crossref PubMed Scopus (1055) Google Z. Huang D. Ni S. et al.Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer.Int J Cancer. 2010; 127: 118-126Crossref PubMed Scopus (868) Google in the L.G. Gu J. Serum is a promising novel marker for early detection of colorectal 2012; PubMed Scopus Google cancer H. Zhang L. et al.Circulating plasma is a novel biomarker for metastatic cancer and One. 2011; PubMed Scopus Google in the Huang et al.Circulating directly from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is with 2010; PubMed Scopus Google in the Y. Kosaka N. M. et as a potential diagnostic marker for 2009; PubMed Scopus Google Zhang K. H. et al.Circulating microRNAs as biomarkers for 2011; PubMed Scopus Google Wang H. et al.Serum as for in with B One. 2011; PubMed Scopus Google not for J. C. X. et al.Circulating and in patients with or 2011; PubMed Scopus Google in the J. L. X. Hu J. et al.Plasma to 2011; PubMed Scopus Google Y. H. H. et al.Circulating as a novel biomarker for 2012; 56: Full Text Full Text PDF PubMed Scopus Google J. Y. X. et al.Serum microRNA as a potential marker for Sci. 2011; PubMed Scopus Google in the J. Chen J. et al.MicroRNAs in plasma of patients as novel blood-based biomarkers of Res. 2009; 2: PubMed Scopus Google A. N. et and and in with circulating and Res. 2010; PubMed Scopus Google in the Huang X. H. et al.Circulating as a novel marker in 2010; PubMed Scopus Google S. K. Chen et expressed miRNAs in the plasma may provide a signature for J Res. 2010; Google N. A. et and serum microRNAs in the and in patients with One. 2011; PubMed Scopus Google R. Komatsu S. Ichikawa D. et diagnostic of circulating in plasma of patients with J Cancer. 2011; 105: PubMed Scopus Google in the J. J. Y. et of plasma microRNAs with serum for early detection of cancer.Int J Cancer. 2011; Scopus Google microRNA colorectal direct esophageal gastric polymerase chain in the in a new microRNA colorectal direct esophageal gastric polymerase chain Zhang et C. Wang C. Chen X. et al.Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma.Clin Chem. 2010; 56: 1871-1879Crossref PubMed Scopus (289) Google Scholar have investigated the serum miRNA profiles of patients with esophageal squamous cell using miRNAs using direct this group identified serum miRNAs and as biomarkers. The under the for the miRNAs were for serum tumor and patients in the early of the could be from using the miRNA C. Wang C. Chen X. et al.Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma.Clin Chem. 2010; 56: 1871-1879Crossref PubMed Scopus (289) Google Scholar plasma from group also the plasma expression of miRNAs that were to be with the development of on found that the plasma of to be in patients in the and the were significantly in compared with A of the in plasma was the of an in serum tumor which that circulating miRNAs may be for diagnosis of in S. Ichikawa D. Takeshita H. et al.Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma.Br J Cancer. 2011; 105: 104-111Crossref PubMed Scopus (233) Google Scholar However, there have been reports regarding circulating miRNAs for the other group first reported the of circulating miRNAs as biomarkers in patients with miRNAs and which have been reported to be in as miRNAs and their in plasma using In the plasma of these miRNAs the tumor miRNA and were significantly in patients in the also found that the plasma of these miRNAs were significantly in compared with M. Ichikawa D. Komatsu S. et al.Circulating microRNAs in plasma of patients with gastric cancers.Br J Cancer. 2010; 102: 1174-1179Crossref PubMed Scopus (578) Google Scholar Liu et R. Zhang C. Hu Z. et al.A five-microRNA signature identified from genome–wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis.Eur J Cancer. 2011; 47: 784-791Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar have investigated the serum miRNA profiles of patients with using miRNAs using direct this group identified serum miRNAs and as biomarkers for found that the expression of serum miRNAs was with the tumor and the for the miRNAs were for serum tumor R. Zhang C. Hu Z. et al.A five-microRNA signature identified from genome–wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis.Eur J Cancer. 2011; 47: 784-791Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar Other groups have investigated serum miRNA profiles using miRNA and concluded that was the biomarker for detection in the serum, with and the expression in primary was compared with normal H. Zhu L. Liu B. et al.Genome-wide microRNA profiles identify miR-–378 as a serum biomarker for early detection of gastric cancer.Cancer Lett. 2012; 316: 196-203Crossref PubMed Scopus (234) Google Scholar The selective release of specific cellular miRNAs from the tumor cells or from normal as could these et E.K. Chong W.W. Jin H. et al.Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening.Gut. 2009; 58: 1375-1381Crossref PubMed Scopus (1055) Google Scholar first reported that circulating miRNAs could be potential noninvasive markers for colorectal cancer patients. This group plasma from patients using a miRNA microarray and found that and were in the plasma of patients and in compared with they demonstrated that the detection of could from other and The was with and an E.K. Chong W.W. Jin H. et al.Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening.Gut. 2009; 58: 1375-1381Crossref PubMed Scopus (1055) Google this has been by other Huang et Z. Huang D. Ni S. et al.Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer.Int J Cancer. 2010; 127: 118-126Crossref PubMed Scopus (868) Google Scholar the plasma of miRNAs that were to be in in This group found that and had a diagnostic for and and that patients with could be from the using these 2 Z. Huang D. Ni S. et al.Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer.Int J Cancer. 2010; 127: 118-126Crossref PubMed Scopus (868) Google Scholar Wang et L.G. Gu J. Serum is a promising novel marker for early detection of colorectal 2012; PubMed Scopus Google Scholar the serum expression of miRNAs and in and metastatic patients and reported that serum had the potential to be a noninvasive biomarker for the early detection of in L.G. Gu J. Serum is a promising novel marker for early detection of colorectal 2012; PubMed Scopus Google Scholar et Huang et al.Circulating directly from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is with 2010; PubMed Scopus Google Scholar reported the first of the direct of circulating miRNAs from the plasma without RNA extraction and found that the direct of plasma could be used as a potential noninvasive diagnostic and prognostic biomarker for Huang et al.Circulating directly from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is with 2010; PubMed Scopus Google Scholar et Y. Kosaka N. M. et as a potential diagnostic marker for 2009; PubMed Scopus Google Scholar first reported the of circulating miRNAs as biomarker for cancer identified as an miRNA of by miRNA profiles in the process of development using of serum was found in the of of patients and the were significantly Y. Kosaka N. M. et as a potential diagnostic marker for 2009; PubMed Scopus Google Scholar et Wang H. et al.Serum as for in with B One. 2011; PubMed Scopus Google Scholar investigated the serum of miRNAs and to identify new but only the was significantly in the serum of patients compared with or viral B patients without and the of were also significantly in serum Wang H. et al.Serum as for in with B One. 2011; PubMed Scopus Google Scholar et J. L. X. Hu J. et al.Plasma to 2011; PubMed Scopus Google Scholar investigated plasma miRNAs using an miRNA microarray in a of patients. This group first on the of the microarray and subsequently identified miRNAs and using for the miRNA reported that their miRNA could patients from B patients and patients and it is a promising marker for the early diagnosis of J. L. X. Hu J. et al.Plasma to 2011; PubMed Scopus Google Scholar Wang et J. Chen J. et al.MicroRNAs in plasma of patients as novel blood-based biomarkers of Res. 2009; 2: PubMed Scopus Google Scholar the plasma of miRNAs and that have been implicated in cancer development in The plasma of miRNA were in patients compared with the The for miRNA were not but they to when the miRNAs were J. Chen J. et al.MicroRNAs in plasma of patients as novel blood-based biomarkers of Res. 2009; 2: PubMed Scopus Google Scholar et A. N. et and and in with circulating and Res. 2010; PubMed Scopus Google Scholar identified 2 of the family and that were in using This group also found that these 2 miRNAs were significantly in the of and patients compared with of and et N. A. et and serum microRNAs in the and in patients with One. 2011; PubMed Scopus Google Scholar identified serum miRNAs and as diagnostic biomarkers of in an circulating miRNAs and demonstrated that the circulating miRNAs could as not only diagnostic markers but also of the Liu et J. J. Y. et of plasma microRNAs with serum for early detection of cancer.Int J Cancer. 2011; Scopus Google Scholar miRNA and in the plasma of and patients using All miRNA were significantly in patients compared with patients and This group concluded that the of and the marker was among various in from and J. J. Y. et of plasma microRNAs with serum for early detection of cancer.Int J Cancer. 2011; Scopus Google Scholar Circulating miRNAs are for use as valuable biomarkers owing to their in the and of Therefore, circulating miRNAs may be used for the clinical in cancer and early or and for the the small of which is a that miRNAs from other for an of using and direct

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  • Journal of Biological Chemistry
  • Maria F Lodeiro + 5 more

We have reconstituted human mitochondrial transcription in vitro on DNA oligonucleotide templates representing the light strand and heavy strand-1 promoters using protein components (RNA polymerase and transcription factors A and B2) isolated from Escherichia coli. We show that 1 eq of each transcription factor and polymerase relative to the promoter is required to assemble a functional initiation complex. The light strand promoter is at least 2-fold more efficient than the heavy strand-1 promoter, but this difference cannot be explained solely by the differences in the interaction of the transcription machinery with the different promoters. In both cases, the rate-limiting step for production of the first phosphodiester bond is open complex formation. Open complex formation requires both transcription factors; however, steps immediately thereafter only require transcription factor B2. The concentration of nucleotide required for production of the first dinucleotide product is substantially higher than that required for subsequent cycles of nucleotide addition. In vitro, promoter-specific differences in post-initiation control of transcription exist, as well as a second rate-limiting step that controls conversion of the transcription initiation complex into a transcription elongation complex. Rate-limiting steps of the biochemical pathways are often those that are targeted for regulation. Like the more complex multisubunit transcription systems, multiple steps may exist for control of transcription in human mitochondria. The tools and mechanistic framework presented here will facilitate not only the discovery of mechanisms regulating human mitochondrial transcription but also interrogation of the structure, function, and mechanism of the complexes that are regulated during human mitochondrial transcription.

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  • Research Article
  • Cite Count Icon 514
  • 10.1074/jbc.r100041200
Coregulator Codes of Transcriptional Regulation by Nuclear Receptors
  • Oct 1, 2001
  • Journal of Biological Chemistry
  • Michael G Rosenfeld + 1 more

hormone response element peroxisome proliferator-activated receptor thyroid hormone receptor estrogen receptor ligand binding domain nuclear receptor corepressor silencing mediator of retinoic acid and thyroid hormone receptor imitation SWI cAMP response element-binding protein CREB-binding protein histone acetyltransferase mitogen-activated protein histone deacetylase steroid receptor coactivator RAR interacting protein glucocorticoid receptor interacting protein T3R receptor associated protein vitamin receptor D interacting protein Members of the nuclear receptor superfamily directly activate or repress target genes by binding to hormone response elements (HREs)1 in promoter or enhancer regions, and by binding to other DNA sequence-specific activators and can inhibit the transcriptional activities of other classes of transcription factors by transrepression. Hormone response elements provide specificity to receptor homodimer heterodimer binding (reviewed in Ref. 2Bourguet W. Germain P. Gronemeyer H. Trends Pharm. Sci. 2000; 21: 381-388Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). Nuclear receptor functions are directed by specific activation domains, referred to as activation function 1 (AF-1), which resides in the N terminus, and activation function 2 (AF-2), which resides in the C-terminal ligand binding domain (LBD) (reviewed in Ref. 1Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar). Regulation of gene transcription by nuclear receptors requires the recruitment of proteins characterized as coregulators, with ligand-dependent exchange of corepressors for coactivators serving as the basic mechanism for switching gene repression to activation. In this review, we discuss biochemical and genetic studies suggesting that coregulatory complexes are differentially utilized in both a cell- and promoter-specific fashion to activate or repress gene transcription. These coregulatory components, themselves targets of diverse intracellular signaling pathways, provide a combinatorial code for tissue- and gene-specific responses, utilizing both enzymatic and platform assembly functions to mediate the actions of nuclear receptor genetic programs critical for developmental and homeostatic processes in metazoan organisms. A diverse group of proteins have emerged as potential coactivators for nuclear receptors. Ligand-dependent recruitment of coactivators is dependent on AF-2, which consists of a short conserved helical sequence within the C terminus of the LBD (2Bourguet W. Germain P. Gronemeyer H. Trends Pharm. Sci. 2000; 21: 381-388Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). Biochemical and expression cloning approaches have been used to identify a large number of factors that interact with nuclear receptors in either a ligand-independent or a ligand-dependent manner and are often components of large multiprotein complexes. Many of these factors are capable of potentiating nuclear receptor activity in transient cotransfection assays. In addition, a distinct set of coactivators is associated with the AF-1 domain. As the number of potential coregulators clearly exceeds the capacity for direct interaction by a single receptor, the most plausible hypothesis is that transcriptional activation by nuclear receptors involves the actions of multiple factors. These factors act in a sequential and/or combinatorial manner to reorganize chromatin templates and to modify and recruit basal factors and RNA polymerase II (3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). As chromatinized transcription units are “repressed” compared with naked DNA, a critical aspect of gene activation involves nucleosomal remodeling (reviewed in Refs. 3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar). Two general classes of chromatin remodeling factors that appear to play critical roles in transcriptional activation by nuclear receptors have been identified. These are ATP-dependent nucleosome remodeling complexes and factors that contain histone acetyltransferase activity. The yeast SWI·SNF complex facilitates the binding of sequence-specific transcription factors to nucleosomal DNA and can cause local changes in chromatin structure in an ATP-dependent manner (3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 6Pazin M.J. Kadonaga J.T. Cell. 1997; 88: 737-740Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar, 8Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J. Wang L. Berger S.L. Kouzarides T. Nakatani Y. Allis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 9Ogryzko V.V. Kotani T. Zhang R.L. Howard S.T. Yang X.J. Howard B.H. Qin J. Nakatani Y. Cell. 1998; 94: 35-44Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 10Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1549) Google Scholar, 11Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar, 12Grant P.A. Duggan L. Cote J. Roberts S.M. Brownell J.E. Candau R. Ohba R. Owen-Hughes T. Allis C.D. Winston F. Berger S.L. Workman J.L. Genes Dev. 1997; 11: 1640-1650Crossref PubMed Scopus (897) Google Scholar). Mammalian homologues of Drosophila SWI2/SNF2 such as BRG1/hBrm function as components of large multiprotein complexes. Transfection of ATPase-defective alleles of either Brg1 orhBrm into several mammalian cell lines leads to a significant decrease in the ability of several nuclear receptors to activate transcription (3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 6Pazin M.J. Kadonaga J.T. Cell. 1997; 88: 737-740Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Remodeling complexes containing ISWI (imitation SWI) may also be involved in nuclear receptor function (7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar, 8Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J. Wang L. Berger S.L. Kouzarides T. Nakatani Y. Allis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 9Ogryzko V.V. Kotani T. Zhang R.L. Howard S.T. Yang X.J. Howard B.H. Qin J. Nakatani Y. Cell. 1998; 94: 35-44Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 10Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1549) Google Scholar, 11Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar). Rates of gene transcription roughly correlate with the degree of histone acetylation, with hyperacetylated regions of the genome appearing to be more actively transcribed than hypoacetylated regions (reviewed in Ref. 7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar). The specific recruitment of a complex with histone acetyltransferase activity to a promoter may play a critical role in overcoming repressive effects of chromatin structure on transcription (4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 6Pazin M.J. Kadonaga J.T. Cell. 1997; 88: 737-740Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar). This concept was further supported by the subsequent finding that the mammalian Gcn5 orthologues, including p/CAF, CREB-binding protein (CBP), adenovirus E1A-binding protein p300, and TAFII250, each possess intrinsic histone acetyltransferase (HAT) activity (7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar, 8Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J. Wang L. Berger S.L. Kouzarides T. Nakatani Y. Allis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 9Ogryzko V.V. Kotani T. Zhang R.L. Howard S.T. Yang X.J. Howard B.H. Qin J. Nakatani Y. Cell. 1998; 94: 35-44Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 10Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1549) Google Scholar, 11Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar). Conversely, the discovery that a mammalian histone deacetylase (HDAC) was a homologue of the yeast corepressor, RPD3 (13Taunton J. Hassig C.A. Schreiber S.L. Science. 1996; 272: 408-411Crossref PubMed Scopus (1569) Google Scholar), gave rise to the hypothesis that regulated activation events might involve the exchange of complexes containing histone deacetylase functions with those containing histone acetyltransferase activity (Fig. 1). It appears that in most cases the acetyltransferases are not directly recruited to nuclear receptors but associate with other coactivators that exhibit higher affinity for the liganded receptor. The acetyltransferase functions of factors such as CBP/p300 are directly required for enhanced transcription on chromatinized templates (14Kraus W. Manning E. Kadonaga J. Mol. Cell Biol. 1999; 19: 8123-8135Crossref PubMed Scopus (203) Google Scholar). A large number of proteins that are recruited in a ligand-dependent fashion have the capacity to enhance transcriptional activation by transient transfection. Several insights into the mechanisms by which coactivator complexes are recruited to nuclear receptors in a ligand-dependent manner have been provided by the initial identification of the p160 family of nuclear receptor coactivators, referred to as SRC-1/NCOA1, TIF2/GRIP1, and p/CIP/A1B1/ACTR/RAC/TRAM-1 (reviewed in Ref. 15McKenna N.J. Lanz R.B. O'Malley B.W. Endocr. Rev. 1999; 20: 321-344Crossref PubMed Scopus (1669) Google Scholar). The p160 factors consist of three members that exhibit a common domain structure, illustrated in Fig. 1. The central conserved domain mediates ligand-dependent interactions with the nuclear receptor LBD, whereas the conserved C-terminal transcriptional activation domains mediate interactions with either CBP/p300 or protein-arginine methyltransferase (16Chen D. Ma H. Hong H. Koh S.S. Huang S.-M. Schurter B.T. Aswad D.W. Stallcup M.R. Science. 1999; 284: 2174-2176Crossref PubMed Scopus (1019) Google Scholar, 17Koh S. Chen D. Lee Y. Stallcup M. J. Biol. Chem. 2001; 276: 1089-1098Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). Based on the presence of three regulatory domains, members of the p160 family have been suggested to function as coactivators, at least in part, by serving as adapter molecules that recruit CBP and/or p300 complexes to promoter-bound nuclear receptors in a ligand-dependent manner (18Kurokawa R. Kalafus D. Ogliastro M.-H. Kioussi C. Xu L. Torchia J. Rosenfeld M.G. Glass C.K. Science. 1998; 279: 700-703Crossref PubMed Scopus (199) Google Scholar, 19Torchia J. Rose D.W. Inostroza J. Kamei Y. Westin S. Glass C.K. Rosenfeld M.G. Nature. 1997; 387: 677-684Crossref PubMed Scopus (1112) Google Scholar). Biochemical studies have also demonstrated strong ligand-dependent interactions between nuclear receptors and p140 factors, probably representing the coregulator RIP140, which results in a reproductive defect in female mice on gene deletion (20White R. Leonaardsson G. Roswell G. Jacobs I. Milligan S. Parker M. Nat. Med. 2000; 6: 1368-1374Crossref PubMed Scopus (165) Google Scholar). Analysis of the nuclear receptor interaction domain of the p160 family led to the identification of three repeated motifs with a consensus sequence LXXLL in which L represents leucine andX represents any amino acid. The LXXLL motif has been found to be necessary and sufficient for ligand-dependent interactions with the nuclear receptor ligand binding domain (19Torchia J. Rose D.W. Inostroza J. Kamei Y. Westin S. Glass C.K. Rosenfeld M.G. Nature. 1997; 387: 677-684Crossref PubMed Scopus (1112) Google Scholar, 21Heery D.M. Kalkhoven E. Hoare S. Parker M.G. Nature. 1997; 387: 733-736Crossref PubMed Scopus (1800) Google Scholar, 22Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V. Nature. 1998; 395: 137-143Crossref PubMed Scopus (1714) Google Scholar, 23Feng W. Ribeiro R.C.J. Wagner R.L. Nguyen H. Apriletti J.W. Fletterick R.J. Baxter J.D. Kushner P.J. West B.L. Science. 1998; 280: 1747-1749Crossref PubMed Scopus (520) Google Scholar, 24Darimont B.D. Wagner R.L. Apriletti J.W. Stallcup M.R. Kushner P.J. Baxter J.D. Fletterick R.J. Yamamoto K.R. Genes Dev. 1998; 12: 3343-3356Crossref PubMed Scopus (834) Google Scholar, 25Shiau A.K. Barstad D. Loria P.M. Cheng L. Kushner P.J. Agard D.A. Greene G.L. Cell. 1998; 95: 927-937Abstract Full Text Full Text PDF PubMed Scopus (2304) Google Scholar). Structural studies of the PPARγ, ER, and T3R ligand binding domains complexed to fragments of the p160 nuclear receptor interaction domains revealed that these motifs form short α helices (22Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V. Nature. 1998; 395: 137-143Crossref PubMed Scopus (1714) Google Scholar, 23Feng W. Ribeiro R.C.J. Wagner R.L. Nguyen H. Apriletti J.W. Fletterick R.J. Baxter J.D. Kushner P.J. West B.L. Science. 1998; 280: 1747-1749Crossref PubMed Scopus (520) Google Scholar, 24Darimont B.D. Wagner R.L. Apriletti J.W. Stallcup M.R. Kushner P.J. Baxter J.D. Fletterick R.J. Yamamoto K.R. Genes Dev. 1998; 12: 3343-3356Crossref PubMed Scopus (834) Google Scholar, 25Shiau A.K. Barstad D. Loria P.M. Cheng L. Kushner P.J. Agard D.A. Greene G.L. Cell. 1998; 95: 927-937Abstract Full Text Full Text PDF PubMed Scopus (2304) Google Scholar), with multiple LXXLL motifs within a single coactivator mediating cooperative interactions with nuclear receptor dimers or heterodimers. The LXXLL helix is oriented and positioned at each end by a “charge-clamp” consisting of a conserved lysine in helix 3 of the ligand binding domain and a conserved glutamate in the AF-2 helix. These residues grip the LXXLL helix so that the internal leucine residues can pack into a hydrophobic pocket in the receptor C terminus. Most nuclear receptor coactivators have proved to contain functionally important LXXLL helices, with additional residues contributing to binding specificity (e.g. Refs. 26McInerney E.M. Rose D.W. Flynn S.E. Westin S. Mullen T.-M. Krones A. Inostroza J. Torchia J. Nolte R.T. Assa-Munt N. Milburn M.V. Glass C.K. Rosenfeld M.G. Genes Dev. 1998; 12: 3357-3368Crossref PubMed Scopus (531) Google Scholar and 27Heery D. Hoare S. J. Biol. Chem. 2001; 276: 6695-6702Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Furthermore, these contacts are sensitive to conformational changes induced by structurally distinct ligands. Many additional factors have been demonstrated to enhance nuclear receptor activity in functional assays, suggesting that they may serve as nuclear receptor coregulators (reviewed in Ref. 1Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar). Biochemical studies and protein-protein interaction screens suggest that many of these proteins function as components of large multiprotein complexes and that additional enzymatic activities may be important for their function. For example, the p160 protein GRIP1 can associate with arginine methyltransferase 1 (CARM1), which potentiates ligand-dependent transcription by several nuclear receptors (16Chen D. Ma H. Hong H. Koh S.S. Huang S.-M. Schurter B.T. Aswad D.W. Stallcup M.R. Science. 1999; 284: 2174-2176Crossref PubMed Scopus (1019) Google Scholar). PRMTI, a second arginine methyltransferase to also functions as a nuclear receptor coactivator S. Chen D. Lee Y. Stallcup M. J. Biol. Chem. 2001; 276: 1089-1098Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). The CBP/p300 coactivators can recruit additional factors with such as the complexes V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar, R. Kalafus D. Ogliastro M.-H. Kioussi C. Xu L. Torchia J. Rosenfeld M.G. Glass C.K. Science. 1998; 279: 700-703Crossref PubMed Scopus (199) Google Scholar). The and of the recruited complexes may distinct acetyltransferases are required by transcription factors on specific gene targets E. Torchia J. Rose D.W. Xu L. Kurokawa R. E.M. Mullen T.M. Glass C.K. Rosenfeld M.G. Science. 1998; 279: PubMed Scopus Google Scholar). 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Rosenfeld M.G. Nature. 1997; 387: PubMed Scopus Google Scholar). appears to be a of either or protein 1 a protein with and functional to the and corepressors M. W. W. E. M. Genes Dev. 2000; 14: PubMed Google Scholar). is also a of the complex M. W. W. E. M. Genes Dev. 2000; 14: PubMed Google Scholar, Y. V. L. Yang W. Glass C. Rosenfeld M. E. Sci. S. A. 2000; PubMed Scopus Google Scholar), as to the specific functions of in A specific conserved corepressor domain of and has also been to be capable of direct interaction with and Zhang J. M.G. Kouzarides T. Genes Dev. 2000; 14: Google Scholar, M. Nature. 1999; PubMed Scopus Google Scholar). In these suggest that with specific corepressor complexes are regulated and exhibit promoter and Two in the C-terminal regions of and appear to function to mediate interactions with thyroid hormone each containing a conserved consensus sequence that mediate interactions with thyroid and retinoic acid receptors M. 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Loria P.M. Cheng L. Kushner P.J. Agard D.A. Greene G.L. Cell. 1998; 95: 927-937Abstract Full Text Full Text PDF PubMed Scopus (2304) Google Scholar), corepressor that coactivators and corepressors are themselves targets of multiple pathways, of which are illustrated in Fig. Regulation of coactivator and corepressor function a for of to specific of sequence-specific transcription factors. For example, the histone acetyltransferase activity of CBP has been suggested to be regulated by which coactivator activities the cell S. S. F. L. P. M. D. A. Nature. 1998; PubMed Scopus Google Scholar). The ability of CBP to serve as a coactivator of is enhanced in response to signaling a mechanism S. H. Science. 1998; PubMed Scopus Google Scholar). The p160 nuclear receptors can be in response to signaling of the to the Rose D.W. F. T. W. D. A. Krones A. K. Rosenfeld R. Glass C.K. Rosenfeld M.G. Sci. S. A. 2000; PubMed Scopus Google Scholar). of lysine residues to LXXLL motifs may the receptors. corepressors are targets of pathways, with activation of with a of a nuclear to a or S. H. Science. 1998; PubMed Scopus Google C. R.J. W. D. Cell. 1999; 98: Full Text Full Text PDF PubMed Scopus Google Scholar). The N terminus of has been to interact with the mammalian homologue of Drosophila in Y. R. H. P. M. D. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), in of Based on cotransfection can mediate a decrease of protein by a The of with nuclear receptors is by cell signaling events that can the and activity of activation of signaling that the of with estrogen receptors in the presence of the on the of the N terminus K. Torchia J. Mullen T.-M. R. M. S. J. C.K. Glass C.K. Rosenfeld M.G. Rose D.W. Sci. S. A. 1998; 95: PubMed Scopus Google Scholar). In addition, with or in of and of with 1 directly interactions between and nuclear receptors or S. M. Mol. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar). Nuclear receptors can serve as or dependent the regulated exchange of binding of factors and characterized by distinct enzymatic and platform In to a ligand-dependent can interactions of specific coregulators with nuclear receptors or mediate their activity or between nuclear or The potential for exchange of nuclear receptors and has for the functional of multiple receptors of coregulatory complexes.

  • Front Matter
  • Cite Count Icon 4
  • 10.1053/j.ajkd.2014.09.009
Retroperitoneal Fibrosis and Asbestosis—A Plausible Association?
  • Nov 13, 2014
  • American Journal of Kidney Diseases
  • Richard D Swartz

Retroperitoneal Fibrosis and Asbestosis—A Plausible Association?

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  • Research Article
  • Cite Count Icon 61
  • 10.1074/jbc.m108675200
A Novel Zinc Finger Protein Interacts with Receptor-interacting Protein (RIP) and Inhibits Tumor Necrosis Factor (TNF)- and IL1-induced NF-κB Activation
  • May 1, 2002
  • Journal of Biological Chemistry
  • Danying Chen + 3 more

Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-kappa B activation. In a yeast two-hybrid screening for potential RIP-interacting proteins, we identified ZIN (zinc finger protein inhibiting NF-kappa B), a novel protein that specifically interacts with RIP. ZIN contains four RING-like zinc finger domains at the middle and a proline-rich domain at the C terminus. Overexpression of ZIN inhibits RIP-, IKK beta-, TNF-, and IL1-induced NF-kappa B activation in a dose-dependent manner in 293 cells. Domain mapping experiments indicate that the RING-like zinc finger domains of ZIN are required for its interaction with RIP and inhibition of RIP-mediated NF-kappa B activation. Overexpression of ZIN also potentiates RIP- and TNF-induced apoptosis. Moreover, immunofluorescent staining indicates that ZIN is a cytoplasmic protein and that it colocalizes with RIP. Our findings suggest that ZIN is an inhibitor of TNF- and IL1-induced NF-kappa B activation pathways.

  • Research Article
  • Cite Count Icon 47
  • 10.1074/jbc.m110.119487
Zyxin-mediated Actin Assembly Is Required for Efficient Wound Closure
  • Nov 1, 2010
  • Journal of Biological Chemistry
  • Thuc Nghi Nguyen + 3 more

Cytoskeletal regulation of cell adhesion is vital to the organization of multicellular structures. The focal adhesion protein zyxin emerged as a key regulator of actin assembly because zyxin recruits Enabled/vasodilator-stimulated phospho-proteins (Ena/VASP) to promote actin assembly. Zyxin also localizes to the sites of cell-cell adhesion and is thought to promote actin assembly with Ena/VASP. Using shRNA targeted to zyxin, we analyzed the roles of zyxin at adhesive contacts. In zyxin-deficient cells, the actin assembly at both focal adhesion and cell-cell adhesion was limited, but their migration rate was unchanged. Cell spreading on E-cadherin-coated surfaces and the formation of cell clusters were slower for zyxin-deficient cells than wild type cells. By ablating a single cell within a cell monolayer, we quantified the rate of wound closure driven by a contractile circumferential actin ring. Zyxin-deficient cells failed to recruit VASP to cell-cell junctions at the wound edge and had a slower wound closure rate than wild type cells. Our results suggest that, by recruiting VASP, zyxin regulates actin assembly at the sites of force-bearing cell-cell adhesion.

  • Research Article
  • Cite Count Icon 14
  • 10.1016/j.ejim.2021.10.006
Electrocardiographic features of patients with COVID-19: One year of unexpected manifestations
  • Oct 14, 2021
  • European Journal of Internal Medicine
  • Fabio Angeli + 10 more

Electrocardiographic features of patients with COVID-19: One year of unexpected manifestations

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  • Cite Count Icon 49
  • 10.1074/jbc.c400502200
Essential Role of IκB Kinase α in the Constitutive Processing of NF-κB2 p100
  • Mar 1, 2005
  • Journal of Biological Chemistry
  • Guoliang Qing + 1 more

Processing of NF-kappaB2 precursor protein p100 to generate p52 is tightly controlled, which is important for proper function of NF-kappaB. Accordingly, constitutive processing of p100, caused by the loss of its C-terminal processing inhibitory domain due to nfkappab2 gene rearrangements, is associated with the development of various lymphomas and leukemia. In contrast to the physiological processing of p100 triggered by NF-kappaB-inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha), which requires the E3 ligase, beta-transducin repeat-containing protein (beta-TrCP), and occurs only in the cytoplasm, the constitutive processing of p100 is independent of beta-TrCP but rather is regulated by the nuclear shuttling of p100. Here, we show that constitutive processing of p100 also requires IKKalpha, but not IKKbeta (IkappaB kinase beta) or IKKgamma (IkappaB kinase gamma). It seems that NIK is also dispensable for this pathogenic processing of p100. These results demonstrate a general role of IKKalpha in p100 processing under both physiological and pathogenic conditions. Additionally, we find that IKKalpha is not required for the nuclear translocation of p100. Thus, these results also indicate that p100 nuclear translocation is not sufficient for the constitutive processing of p100.

  • Research Article
  • Cite Count Icon 37
  • 10.1016/j.cgh.2013.09.052
Quality Measures for Colonoscopy: A Critical Evaluation
  • Oct 2, 2013
  • Clinical Gastroenterology and Hepatology
  • Nabil F Fayad + 1 more

Quality Measures for Colonoscopy: A Critical Evaluation

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  • Research Article
  • Cite Count Icon 83
  • 10.1074/jbc.m109.011494
Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation
  • Aug 1, 2009
  • The Journal of biological chemistry
  • Sarmistha Mukherjee + 4 more

The neurodegenerative disorder spinal and bulbar muscular atrophy or Kennedy disease is caused by a CAG trinucleotide repeat expansion within the androgen receptor (AR) gene. The resulting expanded polyglutamine tract in the N-terminal region of the receptor renders AR prone to ligand-dependent misfolding and formation of oligomers and aggregates that are linked to neuronal toxicity. How AR misfolding is influenced by post-translational modifications, however, is poorly understood. AR is a target of SUMOylation, and this modification inhibits AR activity in a promoter context-dependent manner. SUMOylation is up-regulated in response to multiple forms of cellular stress and may therefore play an important cytoprotective role. Consistent with this view, we find that gratuitous enhancement of overall SUMOylation significantly reduced the formation of polyglutamine-expanded AR aggregates without affecting the levels of the receptor. Remarkably, this effect requires SUMOylation of AR itself because it depends on intact AR SUMOylation sites. Functional analyses, however, indicate that the protective effects of enhanced AR SUMOylation are not due to alterations in AR transcriptional activity because a branched protein structure in the appropriate context of the N-terminal region of AR is necessary to antagonize aggregation but not for inhibiting AR transactivation. Remarkably, small ubiquitin-like modifier (SUMO) attenuates AR aggregation through a unique mechanism that does not depend on critical features essential for its interaction with canonical SUMO binding motifs. Our findings therefore reveal a novel function of SUMOylation and suggest that approaches that enhance AR SUMOylation may be of clinical use in polyglutamine expansion diseases.

  • Research Article
  • Cite Count Icon 12
  • 10.1016/j.fertnstert.2011.07.003
Female overweight is not associated with a higher embryo euploidy rate in first trimester miscarriages karyotyped by hysteroembryoscopy
  • Jul 30, 2011
  • Fertility and Sterility
  • José Bellver + 6 more

Female overweight is not associated with a higher embryo euploidy rate in first trimester miscarriages karyotyped by hysteroembryoscopy

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