Expression In Human Diseases Research Articles

Sleeping Giants: Emerging Roles for the Fat Cadherins in Health and Disease

The vertebrate Fat cadherins comprise a small gene family of four members, Fat1-Fat4, all closely related in structure to Drosophila ft and ft2. Over the past decade, knock-out mouse studies, genetic manipulation, and large sequencing projects has aided our understanding of the function of vertebrate Fat cadherins in tissue development and disease. The majority of studies of this family have focused on Fat1, with evidence now showing it can bind enable (ENA)/Vasodilator-stimulated phosphoprotein (VASP), β-catenin and Atrophin proteins to influence cell polarity and motility; HOMER-1 and HOMER-3 proteins to regulate actin accumulation in neuronal synapses; and scribble to influence the Hippo signaling pathway. Fat2 and Fat3 can regulate cell migration in a tissue specific manner and Fat4 appears to influence both planar cell polarity and Hippo signaling recapitulating the activity of Drosophila ft. Knowledge about the exact downstream signaling pathways activated by each family member remains in its infancy, but it is becoming clearer that they have tissue specific and redundant roles in development and may be lost or gained in cancer. In this review, we summarize the recent progress on understanding the role of the Fat cadherin family, integrating the current knowledge of molecular interactions and tissue distributions, together with the accumulating evidence of their changed expression in human disease. The latter is now beginning to promote interest in these molecules as both biomarkers and new targets for therapeutic intervention.

The Novel miR-7515 Decreases the Proliferation and Migration of Human Lung Cancer Cells by Targeting c-Met

MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression in human diseases, including lung cancer. miRNAs have oncogenic and nononcogenic functions in lung cancer. In this study, we report the identification of a novel miRNA, miR-7515, from lung cancer cells. The novel miR-7515 was characterized using various predictive programs and experimental methods. miR-7515 was able to forming a stem-loop structure and its sequence was conserved in mammals. The expression level of miR-7515 in lung cancer cells and tissues was profiled using TaqMan miRNA assays. miR-7515 was downregulated in lung cancer compared with normal human lung cells and tissues. The target of miR-7515 was determined using a dual luciferase reporter assay. Expression of the target gene was determined by quantitative RT-PCR and Western blot analysis after transfection with miR-7515. miR-7515 directly suppressed human mesenchymal-epithelial transition factor (c-Met) by binding to the 3' untranslated region (UTR). Overexpression of miR-7515 significantly decreased cell-cycle-related proteins downstream of c-Met through c-Met inhibition. Cell proliferation and migration were examined using the XTT proliferation assay and the Transwell migration assay. miR-7515 led to decreased cell proliferation, migration and invasion in a lung cancer cell line. These results suggest that miR-7515 plays an important role in the proliferation and migration of lung cancer cells through c-Met regulation.

Epigenetic Silencing of the Chaperone Cosmc in Human Leukocytes Expressing Tn Antigen

Cosmc is the specific molecular chaperone in the endoplasmic reticulum for T-synthase, a Golgi β3-galactosyltransferase that generates the core 1 O-glycan, Galβ1-3GalNAcα-Ser/Thr, in glycoproteins. Dysfunctional Cosmc results in the formation of inactive T-synthase and consequent expression of the Tn antigen (GalNAcα1-Ser/Thr), which is associated with several human diseases. However, the molecular regulation of expression of Cosmc, which is encoded by a single gene on Xq24, is poorly understood. Here we show that epigenetic silencing of Cosmc through hypermethylation of its promoter leads to loss of Cosmc transcripts in Tn4 cells, an immortalized B cell line from a male patient with a Tn-syndrome-like phenotype. These cells lack T-synthase activity and express the Tn antigen. Treatment of cells with 5-aza-2'-deoxycytidine causes restoration of Cosmc transcripts, restores T-synthase activity, and reduces Tn antigen expression. Bisulfite sequencing shows that CG dinucleotides in the Cosmc core promoter are hypermethylated. Interestingly, several other X-linked genes associated with glycosylation are not silenced in Tn4 cells, and we observed no correlation of a particular DNA methyltransferase to aberrant methylation of Cosmc in these cells. Thus, hypermethylation of the Cosmc promoter in Tn4 cells is relatively specific. Epigenetic silencing of Cosmc provides another mechanism underlying the abnormal expression of the Tn antigen, which may be important in understanding aberrant Tn antigen expression in human diseases, including IgA nephropathy and cancer.

Lef1‐mediated up‐regulation of Epac1 expression in Chronic Lymphocytic Leukemic Cells

Exchange protein activated by cAMP 1 (Epac1), a guanine‐nucleotide exchange factor for the small G‐protein Rap. Contributes to anti‐apoptosis and other cAMP‐mediated actions. Limited previous studies have noted that up‐regulation of Epac1 expression in chronic lymphocytic leukemia (CLL). We assessed peripheral blood mononuclear cells (PBMC) and found that Epac1 mRNA (real‐time PCR) and protein (immunoblotting) are up‐regulated ~70 fold and ~10 fold, respectively, in CLL patients compared to controls. We hypothesized that this increase in Epac1 expression is results from increased transcriptional activity of the Epac1 gene. Deletional analysis of the 2kb promoter region directly upstream of the Epac1 start site revealed that the region necessary for basal expression is located within 100 base pairs of the transcriptional start site. Overexpression of Lef‐1, a transcription factor up‐regulated in CLL, increased activity of a Epac1 promoter luciferase reporter in a CLL cell line but not a normal B‐cell cell line. Stimulation of CLL cells with Wnt3 did not increase activity of the Epac1 promoter reporter but increased activity of a Lef1 luciferase reporter. These results, which indicate that Epac1 is up‐regulated in CLL patients and that Lef1 regulates Epac1 by a non‐cannonical pathway that is unique to the CLL B cells, define a transcriptional mechanism for the regulation of Epac expression in human disease.

Has the Genomic Revolution Failed?

Has the Genomic Revolution Failed?

Gene expression in the Parkinson's disease brain

The study of gene expression has undergone a transformation in the past decade as the benefits of the sequencing of the human genome have made themselves felt. Increasingly, genome wide approaches are being applied to the analysis of gene expression in human disease as a route to understanding the underlying pathogenic mechanisms. In this review, we will summarise current state of gene expression studies of the brain in Parkinson's disease, and examine how these techniques can be used to gain an insight into aetiology of this devastating disorder.

C/EBPβ expression in activated microglia in amyotrophic lateral sclerosis

Neuroinflammation is thought to play a pathogenic role in many neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). In this study we demonstrate that the expression of nitric oxide (NO) synthase-2 (NOS2), and cyclooxygenase (COX)-2 induced by lipopolysaccharide (LPS) with interferon-γ is higher in microglial-enriched cultures from G93A-SOD1 mice, an ALS animal model, than from wild type mice. The levels of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor that regulates proinflammatory gene expression, are also upregulated in activated G93A-SOD1 microglial cells. In vivo, systemic lipopolysaccharide also induces an exacerbated neuroinflammatory response in G93A-SOD1 mice versus wild type mice, with increased expression of glial fibrillary acidic protein (GFAP), CD11b, nitric oxide synthase-2, cyclooxygenase-2, proinflammatory cytokines, and C/EBPβ. Finally, we report that C/EBPβ is expressed by microglia in the spinal cord of ALS patients. This is the first demonstration to our knowledge of microglial C/EBPβ expression in human disease. Altogether these findings indicate that G93A-SOD1 expression results in an exacerbated pattern of neuroinflammation and suggest that C/EBPβ is a candidate to regulate the expression of potentially neurotoxic genes in microglial cells in ALS.

Long-term Selenium Deficiency Increases the Pathogenicity of a Citrobacter rodentium Infection in Mice

Citrobacter rodentium is a mouse pathogen that causes infectious colitis and shares characteristics with human enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli, including the ability to cause attaching and effacing lesions in the colon and serves as a useful model to study the pathogenicity of these bacteria. In this study, mice were fed a selenium-deficient diet for 5 or 20weeks and then infected with C. rodentium. Colonization of the colon by C. rodentium was similar in mice fed adequate or selenium-deficient diets, but total bacterial colonization of the spleen was elevated in mice fed selenium-deficient diet for 20weeks. Infection-induced changes to the colon included inflammatory cell infiltration, gross changes in crypt architecture, and ulceration and denuding of the epithelial layer that were greatest in mice fed a selenium-deficient diet for 20weeks. Expression of pro-inflammatory genes was significantly higher 12-days post-infection in mice fed the selenium-deficient diet for 20weeks compared to mice fed a selenium-adequate diet or selenium-deficient diet for 5weeks. Diarrhea was prevalent in mice fed the selenium-deficient diet for 20weeks but not 5weeks, and this was associated with decreased expression of solute carrier family 26a3 and carbonic anhydrase IV, genes involved in ion transport. These results indicated that selenium played an important role in resistance to the pathological effects of a C. rodentium infection, and therefore, selenium status may be important in the expression of human disease caused by common food-borne bacteria.

Severe Early-Onset Preeclampsia Is Not Associated with a Change in Placental Catechol O-Methyltransferase (COMT) Expression

The genetic deletion of catechol O-methyltransferase (COMT) in mice produces a preeclampsia-like phenotype, with mice exhibiting hypertension, proteinuria, and histological changes, consistent with human pathological features. 2-Methoxyoestradiol, a metabolite of COMT, increases human trophoblast invasiveness in vitro under hypoxic conditions, providing further support that decreased COMT expression may have a role in preeclampsia. However, evidence confirming decreased COMT expression in human disease has been limited to small studies of placentas obtained from cases of term preeclampsia. We examined COMT expression in placentas obtained from healthy term pregnancies (n = 14), preterm normotensive pregnancies (n = 8), and pregnancies complicated by severe preterm preeclampsia (delivery at < 34 weeks' gestation; n = 22). Among our preeclamptic cohort were 10 pregnancies further complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets); and one pregnancy complicated by an eclamptic seizure. COMT expression was analyzed by RT-PCR, Western analysis, and IHC. COMT was mainly expressed in the syncytiotrophoblast. We did not find a significant difference in placental COMT expression in severe preeclampsia compared with either term or preterm normotensive cohorts. Our results suggest that severe preeclampsia may not be associated with a decrease in placental COMT expression.

MicroRNAs: critical mediators of differentiation, development and disease.

MicroRNAs (miRNAs) are small non-coding RNAs that are expressed in higher eukaryoates and have even been found in viral genomes. They usually act as endogenous repressors of target genes by either inhibiting translation, causing mRNA degradation, or by a combination of both mechanisms. More than 850 mature miRNA sequences have been identified in humans, and although this accounts for less than 2% of human genes, it is predicted that 30% of mRNAs are targeted by miRNAs. miRNAs play critical roles in most cellular processes including development, differentiation, and the homeostasis of both a cell and an organism. Moreover, many disease states, including cancer, occur or are sustained by miRNA dysregulation. In this article, the latest reports of miRNA involvement and aberrant expression in human disease are reviewed, with an emphasis on cancer.

MicroRNAs: critical mediators of differentiation, development and disease.

MicroRNAs (miRNAs) are small non-coding RNAs that are expressed in higher eukaryoates and have even been found in viral genomes. They usually act as endogenous repressors of target genes by either inhibiting translation, causing mRNA degradation, or by a combination of both mechanisms. More than 850 mature miRNA sequences have been identified in humans, and although this accounts for less than 2% of human genes, it is predicted that 30% of mRNAs are targeted by miRNAs. miRNAs play critical roles in most cellular processes including development, differentiation, and the homeostasis of both a cell and an organism. Moreover, many disease states, including cancer, occur or are sustained by miRNA dysregulation. In this article, the latest reports of miRNA involvement and aberrant expression in human disease are reviewed, with an emphasis on cancer.

Evolutionary Genetics of Coronary Heart Disease

Nothing in biology makes sense except in the light of evolution.1 — —Theodosius Dobzhanksy, 1973 No biological problem is solved until both the proximate and the evolutionary causation has been elucidated. Furthermore, the study of evolutionary causes is as legitimate a part of biology as is the study of the usually physico-chemical proximate causes.2 — —Ernst W. Mayr, 1982 Susceptibility to common diseases such as coronary heart disease (CHD) may in part reflect historical or evolutionary legacies,3,4 and interest in studying evolutionary biology to gain novel insights into human health and disease is increasing. The evolutionary history of the human species may provide valuable insights into the origin of common diseases beyond what is possible by investigating only the most immediate or “proximal” causes of disease. The potential role of evolutionary biology in explaining disease causation was highlighted by Williams and Nesse3 and is often referred to as darwinian medicine. Although the relevance of an evolutionary perspective may vary depending on the disease under study, a strong argument could be made for studying the evolutionary genetics of CHD, a leading cause of human morbidity and death. Within the last decade, several important advances have made it possible to study “modern” diseases from an evolutionary perspective. The Human Genome Project5 provided a reference human genome, and the subsequent International HapMap Project6,7 described genetic variations (mostly single nucleotide polymorphisms [SNPs]) among individuals and the patterns of variation across the genome. Both projects provide the raw material to study natural selection in the human genome, as reviewed in recent reports.8–10 In addition, sequencing of multiple other genomes, including those of primates, provides a framework for generating important insights into the origin and expression of human diseases.4 Such an avenue of investigation may help answer why, …

Glutathione dysregulation and the etiology and progression of human diseases

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia

Cyclic nucleotide phosphodiesterase (PDE) isoforms can influence disease pathogenesis and be novel therapeutic targets. Because lower cAMP levels may contribute to the decreased apoptosis that occurs in chronic lymphocytic leukemia (CLL), we assessed the expression levels of PDE isoforms in peripheral blood mononuclear cells (PBMC) of healthy adults and patients with CLL. We found a unique PDE mRNA signature in CLL: higher levels than in normal PBMC of PDE7B (increased approximately 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximately 30-fold). Increased PDE7B mRNA in CLL correlates with a 10-fold-higher expression of PDE7B protein and results in an increased contribution of PDE7 to total PDE activity. Consistent with the higher level of PDE7B expression, inhibitors of PDE7 (BRL-50481, IR-202) and a dual PDE4/PDE7 inhibitor (IR-284) selectively increase apoptosis in CLL cells compared with normal PBMC or B cells. Apoptosis of CLL cells promoted by inhibitors of PDE7 and PDE4/7 is attenuated by PKA inhibition, occurs via a mitochondrial-dependent process, and is associated with increased cAMP accumulation and down-regulation of the antiapoptotic protein survivin and of PDE7B. The increase in PDE7B expression and PDE7 inhibitor-promoted apoptosis implicates PDE7B as a drug target in CLL. Our findings identify a unique PDE signature in CLL and illustrate the utility of broad analyses of PDE isoform expression in human disease.

Control of Cellular GADD34 Levels by the 26S Proteasome

GADD34, the product of a growth arrest and DNA damage-inducible gene, is expressed at low levels in unstressed cells. In response to stress, the cellular content of GADD34 protein increases and, on termination of stress, rapidly declines. We investigated the mechanisms that control GADD34 levels in human cells. GADD34 proteins containing either an internal FLAG or a C-terminal green fluorescent protein epitope were degraded at rates similar to endogenous GADD34. However, the addition of epitopes at the N terminus or deletion of N-terminal sequences stabilized GADD34. N-terminal peptides of GADD34, either alone or fused to heterologous proteins, exhibited rapid degradation similar to wild-type GADD34, thereby identifying an N-terminal degron. Deletion of internal PEST repeats had no impact on GADD34 stability but modulated the binding and activity of protein phosphatase 1. Proteasomal but not lysosomal inhibitors enhanced GADD34 stability and eukaryotic initiation factor 2alpha (eIF-2alpha) dephosphorylation, a finding consistent with GADD34's role in assembling an eIF-2alpha phosphatase. GADD34 was polyubiquitinated, and this modification enhanced its turnover in cells. A stabilized form of GADD34 promoted the accumulation and aggregation of the mutant cystic fibrosis transmembrane conductance regulator (CFTRDeltaF508), highlighting the physiological importance of GADD34 turnover in protein processing in the endoplasmic reticulum and the potential impact of prolonged GADD34 expression in human disease.

Expression of SDF-1α and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer

Although stromal cell-derived factor (SDF)-1α and its receptor CXCR4 are experimentally suggested to be involved in tumorigenicity, the clinicopathological significance of their expression in human disease is not fully understood. We examined SDF-1α and CXCR4 expression in colorectal cancers (CRCs) and their related lymph nodes (LNs), and investigated its relationship to clinicopathological features. Specimens of 60 primary CRCs and 27 related LNs were examined immunohistochemically for not only positivity but also immunostaining patterns for SDF-1α and CXCR4. The relationships between clinicopathological features and SDF-1α or CXCR4 expression were then analysed. Stromal cell-derived factor-1α and CXCR4 expression were significantly associated with LN metastasis, tumour stage, and survival of CRC patients. Twenty-nine of 47 CXCR4-positive CRCs (61.7%) showed clear CXCR4 immunoreactivity in the nucleus and a weak signal in the cytoplasm (nuclear type), whereas others showed no nuclear immunoreactivity but a diffuse signal in the cytoplasm and at the plasma membrane (cytomembrane type). Colorectal cancer patients with nuclear CXCR4 expression showed significantly more frequent LN metastasis than did those with cytomembrane expression. Colorectal cancer patients with nuclear CXCR4 expression in the primary lesion frequently had cytomembrane CXCR4-positive tumours in their LNs. In conclusion, expression of SDF-1α and nuclear CXCR4 predicts LN metastasis in CRCs.

Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma

Human APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3) cytidine deaminases have been shown to be potent inhibitors of diverse retroviruses including Vif-deficient human immunodeficiency virus 1 (HIV-1), hepatitis virus B (HBV), adeno-associated virus, and endogenous retroelements. Despite the fact that these enzymes are known to be potential DNA mutators and to target retroviral DNA for cytidine deamination, the pathological effects of their deregulated expression in human diseases are not yet clear. Mutants of the viral HBx protein have been implicated in the carcinogenesis of hepatocellular carcinoma (HCC); however, little is known about how or why such mutants are generated in the human liver. Here, we report that a number of APOBEC3 deaminases preferentially edit the HBx region of HBV DNA and generate C-terminally truncated HBx mutants. Our functional studies indicated that APOBEC3-mediated HBx mutants, especially the C-terminally truncated mutants, cause a gain of function that enhances the colony-forming ability and proliferative capacity of neoplastic cells. Furthermore, we detected G-to-A hypermutation-mediated HBx mutants in preneoplastic liver tissues of selected patients with active chronic HBV infections. We also observed that the APOBEC3B (A3B) cytidine deaminase was widely up-regulated in HCC tumor tissues; it also promoted the growth of neoplastic human HepG2 liver cells and up-regulated heat shock transcription factor1 (HSF1) expression. These findings suggest that some of the APOBEC3 deaminases play a role in the carcinogenesis of HCC through the generation of HBx mutants, providing preneoplastic and neoplastic hepatocytes with a selective clonal growth advantage. Deregulated expression of A3B in liver tissues may also have the potential to promote genetic instability and tumorigenesis.

Down-regulation of 1D-myo-inositol 1,4,5-trisphosphate 3-kinase A protein expression in oral squamous cell carcinoma

Functional proteomics is a useful method to explore changes in protein expression in human diseases, including carcinomas. To identify tumor-associated proteins as biomarkers or molecular targets of human oral squamous cell carcinomas (OSCCs), we performed two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Comparison of the protein expression profiles of OSCC cell lines and normal oral keratinocytes identified six proteins with markedly different expression levels. Of the six proteins, we found a 1D-myo-inositol 1,4,5-trisphosphate 3-kinase A (ITPKA) protein that was down-regulated in OSCC cell lines. ITPKA phosphorylates inositol 1,4,5-trisphosphate, which regulates the calcium (Ca2+) level within the cell by releasing Ca2+ from intracellular stores, and is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling. Western blots revealed dramatically down-regulated ITPKA expression in all OSCC cell lines examined. Real-time quantitative reverse transcriptase-polymerase chain reaction showed down-regulated ITPKA mRNA expression in nine of 12 (75%) OSCC cell lines. Immunohistochemistry analysis showed that 40 of 100 OSCC clinical samples had a significant decrease in ITPKA. Poorly differentiated tumors showed significantly lower immunoreactivity of the protein compared to well- and moderately-differentiated tumors. These data suggest that ITPKA may be related to carcinogenesis by the modulation of inositol polyphosphates and Ca2+ homeostasis and that ITPKA may be a potential novel molecular target, biomarker, parameter, or all of these of cellular differentiation and of intracellular Ca2+ homeostatic characteristics in clinical medicine.

The Heme-Bach1 Pathway in the Regulation of Oxidative Stress Response and Erythroid Differentiation

Heme--as a prosthetic group of proteins required for oxygen transport and storage, respiration, and biosynthetic pathways--is essential for practically all forms of life. Additionally, the degradation products of heme (i.e., carbon monoxide, biliverdin, and bilirubin) produced by the enzymatic actions of heme oxygenase (HO) and biliverdin reductase, possess various biological activities in vivo. In mammalian cells, heme also functions as an intracellular regulator of gene expression by virtue of its ability to bind to Bach1, a transcription factor that functions in association with small Maf proteins. Normally, such complexes function as repressors by binding to specific target sequences, the Maf recognition element (MARE), within enhancers of genes encoding proteins such as HO-1 and beta-globin. By binding to Bach1, heme induces selective removal of the repressor from the gene enhancers permitting subsequent occupancy of the MAREs by activators that, interestingly, also contain small Maf proteins. Thus small Maf proteins play dual functions in gene expression: complexes with Bach1 repress MARE-dependent gene expression, whereas heterodimers with NF-E2 p45 or related factors (Nrf1, Nrf2, and Nrf3) activate MARE-driven genes. By modulating the equilibrium of the small Maf heterodimer network, heme regulates expression of the cytoprotective enzyme HO-1 during the stress response and of beta-globin during erythroid differentiation. Implications of such heme-regulated gene expression in human diseases including atherosclerosis are discussed.

SOCS1: a potent and multifaceted regulator of cytokines and cell‐mediated inflammation

Suppressor of cytokine signalling-1 (SOCS1), as the name implies, is a protein that functions as a negative regulator of cytokine signalling. Initially characterized for its ability to inhibit JAK phosphorylation and function, SOCS1 also targets proteins for degradation by the proteosome machinery. The expression of SOCS1 can be regulated at the transcription, translation and protein level. Despite the broad spectrum of cytokines that can induce SOCS1 expression and/or be inhibited by SOCS1 in vitro, the use of genetically modified mice has revealed a more specific role for SOCS1 in vivo including a critical role in the regulation of IFNgamma signalling. In addition, SOCS1 has a complex role in T cell activation, and studies have revealed significant roles for SOCS1 in the regulation of IL-4, IL-12 and IL-15 in vivo. Interestingly, SOCS1 action is not limited to the regulation of the classical JAK/STAT-signalling pathway, because SOCS1 also inhibits cytokines like insulin and toll-like receptor signal transduction, neither of which activates the JAK/STAT pathway. Evidence is emerging for a role for aberrant SOCS1 expression in human disease, particularly in a number of malignancies.