Control Of Normal Cell Growth Research Articles

Analyzing epigenetic control of galectin expression indicates silencing of galectin-12 by promoter methylation in colorectal cancer.

Galectins, a class of lectins with specificity for ß-galactoside containing glycoconjugates, modulate several cellular processes that are involved in the control of normal cell growth, differentiation, cell-cell, and cell matrix interactions. Pathological alterations of the galectin expression pattern have been implicated in the development and progression of cancer. We therefore analyzed epigenetic mechanisms for control of galectin expression in 9 colorectal cancer (CRC) cell lines. Our data demonstrate that expression of galectins-1, -2, -7, -8, and -9 can be regulated by histone acetylation in CRC cell lines. In addition, the same set of galectins was also found to be modulated by DNA methylation. Of particular note, galectin-12 is silenced in all tested CRC cell lines but known to be re-expressed upon butyrate-induced differentiation and present in normal colonic mucosa. Loss of galectin-12 expression in undifferentiated CRC cells is associated with promoter hypermethylation and for the first time we provide detailed methylation analysis of the promoter region. In CRC tumor tissue, galectin-12 expression was downregulated in 66% of CRC tissue specimens as compared to adjacent normal tissue hinting to a possible tumor-suppressing function in CRC. © 2017 IUBMB Life, 69(12):962-970, 2017.

Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases

The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes.

MYC Acts via the PTEN Tumor Suppressor to Elicit Autoregulation and Genome-Wide Gene Repression by Activation of the Ezh2 Methyltransferase

The control of normal cell growth is a balance between stimulatory and inhibitory signals. MYC is a pleiotropic transcription factor that both activates and represses a broad range of target genes and is indispensable for cell growth. Whereas much is known about gene activation by MYC, there is no established mechanism for the majority of MYC-repressed genes. We report that MYC transcriptionally activates the PTEN tumor suppressor in normal cells to inactivate the phosphoinositide 3-kinase (PI3K) pathway, thus suppressing AKT activation. Suppression of AKT enhances the activity of the EZH2 histone methyltransferase, a subunit of the epigenetic repressor Polycomb Repressive Complex 2 (PRC2), while simultaneously stabilizing the protein. MYC-mediated enhancement in EZH2 protein level and activity results in local and genome-wide elevation in the repressive H3K27me3 histone modification, leading to widespread gene repression including feedback autoregulation of the MYC gene itself. Depletion of either PTEN or EZH2 and inhibition of the PI3K/AKT pathway leads to gene derepression. Importantly, expression of a phospho-defective EZH2 mutant is sufficient to recapitulate nearly half of all MYC-mediated gene repression. We present a novel epigenetic model for MYC-mediated gene repression and propose that PTEN and MYC exist in homeostatic balance to control normal growth, which is disrupted in cancer cells.

Abstract 1939: Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells

Abstract Translational control is a crucial component of cancer development and progression. Eukaryotic initiation factor 4E (eIF4E) mediates eIF4F association with the mRNA 5’ cap structure to stimulate cap-dependent translation initiation. The eIF4E-binding protein, 4E-BP1, regulates cap-dependent translation through its phosphorylation at multiple sites. The search for new kinases that could be implicated in 4E-BP1 phosphorylation, and determination of the mechanisms that affect 4E-BP1 stability are important to understand the role of eIF4E in cell transformation. In this study, we investigate 48 kinases that may be implicated in 4E-BP1 phosphorylation and stability. The screening study was based on analysis of 4E-BP1 status after inhibition of these kinases in a breast carcinoma cell line (MDA-MB 231 cells). With the use of this method, several kinases that affect 4E-BP1 stability (LRRK2, RAF-1, p38γ, GSK3β, AMPKα, PRKACA and PRKACB) and 4E-BP1 phosphorylation (CDK1, PDK1, SRC, PRKCB1, PAK2, p38β PRKCA and CaMKKB) were identified. These novel findings provide evidence that 4E-BP1 can be regulated and stabilized by multiple kinases implicated in several cell signaling pathways. We also found that LRRK2 downregulation affects 4E-BP1 stability and causes degradation of this factor in various cell types. Interestingly, inhibition of proteasome activity by MG132 restored total 4E-BP1 protein levels in cells where LRRK2 was downregulated. In addition, these stabilization events appear to be functionally important for cell growth control in normal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1939. doi:10.1158/1538-7445.AM2011-1939

Cancer Epigenomics: a review

Epigenetic inactivation of genes that are crucial for the control of normalcell growth is a hallmark of cancer cells. Epigenetic modifications of the DNA do not alter the nucleotide sequence instead they involve the regulation of gene transcription and DNA methylation. Hypermethylation or histone deacetylation, which is within the promoter of a tumor suppressor gene, leads to the silencing as well as a deletion or a mutation of thatgene. Cancer cells often show aberrant methylation and the frequency of aberrations increases is seen with the progression of disease. Hypermethylation events can occur early in tumorogenesis, involving the disruption of pathways that may predispose cells to malignant transformation. Epigenetic modification such as DNA methylation can be exploited for clinical purposes in cancer patients, first using hypermethylation as a molecular biomarker of cancer cells and second, epigenetic changes which are potentially reversible.

Analysis of select members of the E26 (ETS) transcription factors family in colorectal cancer

The E-twenty-six (ETS) family of transcription factors is known to act as positive or negative regulators of the expression of genes that are involved in diverse biological processes, including those that control cellular proliferation, differentiation, hematopoiesis, apoptosis, metastasis, tissue remodeling, and angiogenesis. Identification of target gene promoters of normal and oncogenic transcription factors provides new insights into the regulation of genes that are involved in the control of normal cell growth and differentiation. The aim of the present investigation was to analyze the differential expression of 11 ETS (ELF-3, ESE3, ETS1, ETV3, ETV4, ETV6, NERF, PDEF, PU1, Spi-B, and Spi-C) as potential markers for prognostic of colorectal cancer. A series of paired tissue biopsies consisting of a tumor and a non-affected control sample were harvested from 28 individuals suffering from diagnosed colorectal lesions. Total RNA was isolated from the samples, and after reverse transcription, differential expression of the select ETS was carried out through real-time polymerase chain reaction. Tumor staging as determined by histopathology was carried out to correlate the degree of tumor invasiveness with the expression of the ETS genes. The results demonstrated a different quantitative profile of expression in tumors and normal tissues. ETV4 was significantly upregulated with further increase in the event of lymph node involvement. PDEF and Spi-B presented downregulation, which was more significant when lymph node involvement was present. These findings were supported by immunohistochemistry of tumoral tissues. The results suggest that select ETS may serve as potential markers of colorectal cancer invasiveness and metastasis.

A class of DNA-binding peptides from wheat bud causes growth inhibition, G2 cell cycle arrest and apoptosis induction in HeLa cells

BackgroundDeproteinized DNA from eukaryotic and prokaryotic cells still contains a low-molecular weight peptidic fraction which can be dissociated by alkalinization of the medium. This fraction inhibits RNA transcription and tumor cell growth. Removal from DNA of normal cells causes amplification of DNA template activity. This effect is lower or absent in several cancer cell lines. Likewise, the amount of active peptides in cancer cell DNA extracts is lower than in DNA preparation of the corresponding normal cells. Such evidence, and their ubiquitous presence, suggests that they are a regulatory, conserved factor involved in the control of normal cell growth and gene expression.ResultsWe report that peptides extracted from wheat bud chromatin induce growth inhibition, G2 arrest and caspase-dependent apoptosis in HeLa cells. The growth rate is decreased in cells treated during the S phase only and it is accompanied by DNA damage and DNA synthesis inhibition. In G2 cells, this treatment induces inactivation of the CDK1-cyclin B1 complex and an increase of active chk1 kinase expression.ConclusionThe data indicate that the chromatin peptidic pool inhibits HeLa cell growth by causing defective DNA replication which, in turn, arrests cell cycle progression to mitosis via G2 checkpoint pathway activation.

Expression of transforming acidic coiled‐coil containing protein 3 is a novel independent prognostic marker in non‐small cell lung cancer

Transforming acidic coiled-coil containing protein 3 (TACC3) is known to be involved in the control of normal cell growth and differentiation and in mechanisms of unregulated growth leading to tumorigenesis. The aim of the present paper was to determine the rate of TACC3 expression in a non-small cell lung cancer (NSCLC) collection and to clarify its correlation with clinicopathological parameters. A total of 163 NSCLC were analyzed immunohistochemically using a polyclonal TACC3 antibody and monoclonal p53 and Ki-67 antibodies on NSCLC tissue microarrays. A high level of TACC3 expression was observed in 14.8% of cases, preferentially squamous cell carcinomas. Patients whose tumors had a high TACC3 expression had a significantly shorter median survival time. In the Cox regression-based multivariate analysis, TACC3 expression proved to be an independent prognostic parameter (P = 0.031). TACC3 expression was correlated with p53 expression, and patient whose tumors highly expressed TACC3 and p53 had a significantly poorer prognosis than patients whose tumors had low-level expression for both immunostainings (P = 0.006). It is suggested that increase in TACC3 may impart a proliferative advantage to NSCLC and contribute to tumor progression, and that TACC3 expression is a strong prognostic indicator of clinical outcome in NSCLC.

ETS transcription factors and their emerging roles in human cancer

Cancer can be defined as a genetic disease, resulting as a consequence of multiple events associated with initiation, promotion and metastatic growth. Cancer results from the loss of control of cellular homeostasis. Cell homeostasis is the result of the balance between proliferation and cell death, while cellular transformation can be viewed as a loss of relationship between these events. Oncogenes and tumour suppressor genes act as modulators of cell proliferation, while the balance of apoptotic and anti-apoptotic genes controls cell death. All cancer cells acquire similar sets of functional capacities: (1) independence from mitogenic/growth signals; (2) loss of sensitivity to “anti-growth” signals; (3) evade apoptosis; (4) Neo-angiogenic conversion; (5) release from senescence; and (6) invasiveness and metastasis [Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000, 100, 57–70]. One of the goals of molecular biology is to elucidate the mechanisms that contribute to the development and progression of cancer. Such understanding of the molecular basis of cancer will provide new possibilities for: (1) earlier detection as well as better diagnosis and staging of disease with detection of minimal residual disease recurrences and evaluation of response to therapy; (2) prevention; and (3) novel treatment strategies. We feel that increased understanding of ETS-regulated biological pathways will directly impact these areas. ETS proteins are transcription factors that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis. Identification of target genes that are regulated by a specific transcription factor is one of the most critical areas in understanding the molecular mechanisms that control transcription. Furthermore, identification of target gene promoters for normal and oncogenic transcription factors provides insight into the regulation of genes that are involved in control of normal cell growth, and differentiation, as well as provide information critical to understanding cancer development. This review will highlight the current understanding of ETS genes and their role in cancer.

Role of Polycomb Group Proteins in Stem Cell Self-Renewal and Cancer

Polycomb group proteins (PcG) form part of a gene regulatory mechanism that determines cell fate during normal and pathogenic development. The mechanism relies on epigenetic modifications on specific histone tails that are inherited through cell divisions, thus behaving de facto as a cellular memory. This cellular memory governs key events in organismal development as well as contributing to the control of normal cell growth and differentiation. Consequently, the dysregulation of PcG genes, such as Bmi1, Pc2, Cbx7, and EZH2 has been linked with the aberrant proliferation of cancer cells. Furthermore, at least three PcG genes, Bmi1, Rae28, and Mel18, appear to regulate self-renewal of specific stem cell types suggesting a link between the maintenance of cellular homeostasis and tumorigenesis. In this review, we will briefly summarize current views on PcG function and the evidence linking specific PcG proteins with the behavior of stem cells and cancer cells.

Activated Cdc42 Sequesters c-Cbl and Prevents EGF Receptor Degradation

Cdc42 is a Ras-related protein that has been implicated in the control of normal cell growth, and when improperly regulated, in cellular transformation and invasiveness. A variety of extracellular stimuli, including epidermal growth factor (EGF), activate Cdc42. Here, we show that activation of Cdc42 protects the EGF receptor from the negative regulatory activity of the c-Cbl ubiquitin ligase. Activated Cdc42 binds to p85Cool-1 (for cloned-out-of-library)/β-Pix (for Pak-interactive exchange factor), a protein that directly associates with c-Cbl. This inhibits the binding of Cbl by the EGF receptor and thus prevents Cbl from catalyzing receptor ubiquitination. The role played by Cdc42 in regulating the timing of EGF receptor-Cbl interactions is underscored by the fact that constitutively active Cdc42(F28L), by persistently blocking the binding of Cbl to these receptors, leads to their aberrant accumulation and sustained EGF-stimulated ERK activation, thus resulting in cellular transformation.

Isolation of target gene promoter/enhancer sequences by whole genome PCR method.

AbstractRegulation of gene expression is controlled through the combinatorial action of multiple transcription factors, which function to activate or repress transcription via binding to cis-regulatory elements. Such regulatory elements are usually present in the promoter sequences located upstream of the transcription initiation sites of a target gene. Identification of functional target gene promoters that are regulated by a specific transcription factor is one of the most critical areas in understanding the molecular mechanisms that control transcription. Furthermore, identification of target gene promoters for normal and oncogenic transcription factors provides insight into the regulation of genes that are involved in control of normal cell growth and differentiation, as well as provide information critical to understanding cancer development.KeywordsElectrophoretic Mobility Shift AssaySpecific Transcription FactorTarget Gene PromoterOncogenic Transcription FactorGenome Polymerase Chain ReactionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer.

Proto oncogenes represent a family of genes which when activated have been shown to play a role in the pathogenesis of a number of malignancies in vertebrate species including humans.1,2 In physiologic states these same genes are known to play a role in the normal cell growth control and differentiation. The HER2/neu gene is a member of the Type I receptor tyrosine kinase (RTK) group which is one of the subfamilies in the proto oncogene family and encodes a 185kD surface membrane receptor protein. This gene has been localized to chromosome 17q21,1 and the encoded protein is expressed in a wide variety of tissues including the skin, oral mucera, breast, ovary, endometrium, lung, liver, pancreas, small and large bowel, kidney, bladder and the central nervous system as well as some connective tissues.4–5 The exact physiological role of the HER2/neu protein in these tissues is not completely understood, but like other proto oncogenes it is believed to play an important signaling role in cellular proliferation and differentiation processes. Current data suggests that it forms hetero-dimers with other members of the RTKI family (such as HER 1, HER3 and HER4 in response to various ligands known as heregulins.6–8 Activation of HER2/neu results in an increase its kinase activity which in turn initiates signal transduction resulting in either cellular proliferation and/or differentiation, depending on the ligand as well as the conditions.9–14 In human breast cancers, a non-inherited alteration occurs in this gene in 25–30% of cases.

Genetic and epigenetic changes of intercellular communication genes during multistage carcinogenesis.

During multistage carcinogenesis, the functions of several key genes involved in cell growth control must be damaged. Such genes include not only those involved in cell cycle control of individual cells, but also those involved in the coordination of cell growth throughout a given tissue through cell-cell communication. The most intimate form of intercellular communication is mediated by gap junctions. Gap junctional intercellular communication (GJIC) is known to transfer small water soluble molecules, including cAMP and IP3, from the cytoplasm of one cell to that of its neighbors; the growth of a given GJIC-associated cell is thus kept in check by other GJIC-connected cells. Most tumor cells have a reduced ability to communicate among themselves and/or with surrounding normal cells, confirming the importance of intact GJIC in growth control. When connexin (gap junction protein) genes are transfected into such cells, normal cell growth control is often recovered. Certain dominant-negative mutant connexin genes can reverse such tumor suppression. While these results suggest that connexin genes form a family of tumor suppressor genes, so far we have found no connexin gene mutations in human tumors; only two connexin gene mutations were found in chemically induced rat tumors. On the other hand, our recent studies suggest that connexin genes may be inactivated by hypermethylation of their promoter regions, suggesting that epigenetic inactivation of connexin genes may be a mechanism of GJIC disturbance in certain tumors. However, in many tumor cells connexins are normally expressed but aberrantly localized. The mechanisms of aberrant localization of connexins include lack of an appropriate cell-cell recognition apparatus and aberrant phosphorylation of connexins. These results suggest that GJIC disorders may occur not only because of aberrant expression of connexin genes themselves, but also as a result of disruption of various control mechanisms of the protein functions.

Ras Enhances Myc Protein Stability

Various experiments have demonstrated a collaborative action of Myc and Ras, both in normal cell growth control as well as during oncogenesis. We now show that Ras enhances the accumulation of Myc activity by stabilizing the Myc protein. Whereas Myc has a very short half-life when produced in the absence of mitogenic signals, due to degradation by the 26S proteasome, the half-life of Myc increases markedly in growth-stimulated cells. This stabilization is dependent on the Ras/Raf/MAPK pathway and is not augmented by proteasome inhibition, suggesting that Ras inhibits the proteasome-dependent degradation of Myc. We propose that one aspect of Myc–Ras collaboration is an ability of Ras to enhance the accumulation of transcriptionally active Myc protein.

Growth control of 3T3 fibroblast cell lines established from connexin 43-deficient mice.

Connexins are considered to be involved in cell growth control, on the basis of studies mainly with tumorigenic cells. To study the role of connexin genes in normal cell growth control, we established fibroblast cell lines from connexin 43 (Cx43)-deficient mice and characterized their growth. Embryonic fibroblasts from wild-type mice (Cx43+/+) and those with heterozygous (Cx43+/-) and homozygous (Cx43+/-) deficiencies of the Cx43 gene were cultured and passaged by a 3T3 protocol (every 3 d, 3 x 10(5) cells/60-mm dish). All cell lines showed a growth crisis during passages 6-15 and then started to grow well. All cell lines grew at similar rates under the 3T3 protocol, but Cx43-deficient (Cx43-/-) cell lines tended to grow faster when they were plated at 10(5) cells per dish. Cx43-/- cells did not express Cx43 and showed little gap-junctional intercellular communication (GJIC), confirming that Cx43 is the major connexin responsible for GJIC of these fibroblasts. While all Cx43+/+ and Cx43+/- cell lines expressed Cx43 protein, some of them showed very little GJIC. Those cell lines with high GJIC showed higher levels of the P2 form of Cx43 protein, and more Cx43 was localized in the plasma membrane than in cell lines with lower GJIC levels. We investigated effects of serum concentration on cell growth in these cell lines. Although different cell lines responded differentially to these agents, there was no clear relationship between Cx43 expression and cell growth stimulation by them. This suggests that Cx43 expression alone is not a strong regulator of mouse fibroblast growth.

Traps to catch unwary oncogenes

The MYC proto-oncogene has long been implicated in the control of normal cell growth and its deregulation is associated with the development of neoplasia. The MYC protein has a well-established role as a component of signal-transduction pathways promoting both proliferation and apoptosis. Because signalling pathways that drive cell death and cell proliferation are so tightly coupled, a synergy between genetic lesions leading to suppression of cell death and those promoting cell proliferation is observed during carcinogenesis. We discuss such synergy with respect to the cooperating oncogenes MYC, RAS and BCL2.

Antiproliferative effect of c-myc antisense phosphorothioate oligodeoxynucleotides in malignant glioma cells.

To improve the prognosis for primary malignant tumors of the central nervous system, new therapeutic strategies are needed. Antisense oligodeoxynucleotides (ODNs) offer the potential to block the expression of specific genes within cells. The proto-oncogene c-myc has long been implicated in the control of normal cell growth and its deregulation in the development of neoplasia. We therefore reasoned that a strategy using ODNs complementary to c-myc messenger ribonucleic acid would be a potent inhibitor of glioma cell proliferation. A variety of antisense, sense, and scrambled (15-mer) phosphorothioate ODNs targeted to rat and human c-myc messenger ribonucleic acid were synthesized and added to the media of cultured RT-2 cells (a rat glioblastoma cell line). Cell growth was assessed by 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide dye assay 1 to 5 days after adding the ODNs. c-Myc protein expression was analyzed by Western blot analysis. The stability of the ODNs was confirmed by gel electrophoresis. Compared with cultures containing standard media, two of three antisense ODNs significantly inhibited the growth of glioma cells, whereas sense and scrambled sequence ODNs did not significantly affect cell growth at the concentrations tested. A human c-myc antisense sequence, which differed from the rat sequence by one base substitution, also had an inhibitory effect on RT-2 cells. Western blot analysis demonstrated that expression of immunoreactive c-Myc protein was also greatly reduced in the rat antisense ODN-treated cells (and not in sense-, scrambled-, or control-treated cells). The degree of reduction of c-Myc protein expression correlated well with the decrease in cell growth observed with several antisense ODNs. Phosphorothioate ODNs were stable in cell culture media for at least 5 days. These results suggest that c-Myc plays a critical role in glioma cell proliferation and demonstrate that antisense ODNs can suppress proto-oncogene expression and inhibit the proliferation of glioma cells. Our results indicate that the antiproliferative activity of these ODNs was mediated predominantly through sequence-specific antisense mechanisms, but that sequence-specific nonantisense effects may also contribute to the strongest effects demonstrated. These findings support a potential role for antisense strategies designed to inhibit c-myc expression in the treatment of malignant gliomas.

Inhibition of cell proliferation by an RNA ligand that selectively blocks E2F function.

The control of cell proliferation is of central importance to the proper development of a multicellular organism, the homeostatic maintenance of tissues, and the ability of certain cell types to respond appropriately to environmental cues. Disruption of normal cell growth control underlies many pathological conditions, including endothelial proliferative disorders in cardiovascular disease as well as the development of malignant tumors. Particularly critical for the control of cell growth is the pathway involving the G1 cyclin-dependent kinases that regulate the Rb family of proteins, which in turn control E2F transcription factor activity. Because E2F is critical for regulation of cell proliferation, we sought to identify and to develop specific inhibitors of E2F function that might also be useful in the control of cellular proliferation. Moreover, because the control of E2F activity appears to be the end result of G1 regulatory cascades, the ability to inhibit E2F may be particularly effective in impeding a wide variety of proliferative events. We have used in vitro selection to isolate several unique RNA species from high complexity RNA libraries that avidly bind to the E2F family of proteins. These RNAs also inhibit the DNA binding capacity of the E2F proteins. We also show that an E2F RNA ligand can block the induction of S phase in quiescent cells stimulated by serum addition. As such, these data demonstrate the critical role for E2F activity in cell proliferation and suggest that such RNA molecules may be effective as therapeutic entities to control cellular proliferation.

Transcription factors as drug targets in cancer.

Within multicellular organisms, cells are continually signalling to each other to keep in tune with their environment. The ultimate targets for the majority of these signal pathways are upstream transcription factors, whose activity is thereby modulated, resulting in a new pattern of gene expression suitably coupled to the needs of the cell. It has been estimated that up to 10% of human genes may encode transcription factors, thus emphasising how fundamental the control of gene expression is to the processes of cellular division and differentiation during normal development. As a corollary of this, transcriptional regulation can also profoundly affect the course of growth-related diseases such as cancer. Of course it has been realised for some time that the normal counterparts of many oncogenes are transcription factors whose proper role is in the control of normal cell growth. More recent work has begun to identify several other transcription factors which may play a role in cancer, and strategies are now being developed which are designed to use our growing knowledge of transcriptional control mechanisms in the development of novel cancer therapies.