Protooncogenic transcription factors

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Growth factor signaling typically leads to the induction of transcription factors that induce the expression of cell cycle-promoting genes. Transcription factors are modular proteins composed of DNA-binding domains, which interact with cognate DNA sequences, and activation domains, which interact with other proteins to stimulate transcription. The binding of a transcription factor to its cognate DNA sequence enables the RNA Polymerase to locate the proper initiation site. The DNA-binding domains contain specific motifs, typically characterized by consensus amino acid sequences, that define the families of homeodomain proteins, zinc finger transcription factors, winged-helix proteins, HLH proteins, leucine zippers, and nuclear receptors. The activation domains induce transcription in conjunction with the DNA-binding domains and exhibit considerable structural diversity (Figure 3.1.4. A). Acidic activation domains exist as unstructured, random-coil regions until they interact with a coactivator protein. This interaction induces the activation domain to fold into an amphipathic a-helix that contacts a complementary surface of the coactivator protein. In contrast to the relatively short, random-coil acidic activation domains, some activation domains are larger and more structured.

The ligand-binding domains of some nuclear receptors function as activation domains when they engage their specific ligand. This induces a large conformational change that allows the ligand-bind-ing domain with bound hormone to interact with other proteins. Promoters and enhancers are always on the same strand of DNA as the gene they regulate. Consequently, promoters are referred to as cis-acting elements. Transcription factors are sometimes called trans-acting factors because they may be encoded by a gene on a DNA molecule other than that containing the gene being regulated.

Some transcription factors, including C4 zinc finger proteins, basic zipper proteins, HLH proteins, and nuclear receptors, bind to DNA as dimeric units. In some cases, each monomer has a DNA-binding domain with equivalent sequence specificity. In these proteins, heterodimer formation allows the activation domains associated with each monomer to be brought together in a single transcription factor. However, if the monomers have different DNA-binding specificity, the formation of heterodimers increases the range of DNA sequences that a family of factors can bind to. This combinatorial complexity expands both the number of DNA sites, from which these factors can activate transcription, and the ways, in which they can be regulated.

There are three basic routes of activation for proto-oncogenic transcription factors. Some reside in the cytoplasm and shuttle into the nucleus upon binding to a ligand that diffuses into the cells. This is characteristic of nuclear receptors. Others are resident nuclear proteins that are activated by serine kinase cascades. This includes JUN [Vogt et al. 1987], which is activated by phosphorylation on serines 63 and 73. Some transcription factors form latent cytoplasmic complexes that are disrupted in response to certain signaling pathways and cause the transcription factors to translocate into the nucleus. STATs are in this group.

In cancer, aberration in the synthesis or activity of specific transcription factors may suffice to mediate uncontrolled growth.

Homeodomain Proteins. Homeodomain transcription factors contain in their DNA-binding region a conserved structural sequence motif of about 60 amino acids, known as the homeodomain. It is encoded by 180 base pairs, referred to as the home-obox. They target homeotic genes, which specify the differentiation and location of developing

Leucine zipper Holw-loop-hel«

Figure 3.1.4.A. Basic structures of transcription factors. The three-dimensional structures of gene regulatory proteins usually possess axes of symmetry, often accomplished through dimer formation. They contain specific motifs for interacting with DNA, including the helix-turn-helix motif, the zinc finger motif, the leucine zipper motif, and the helix-loop-helix motif. [Reproduced from McKee and McKee 2003. With permission.]

Leucine zipper Holw-loop-hel«

Figure 3.1.4.A. Basic structures of transcription factors. The three-dimensional structures of gene regulatory proteins usually possess axes of symmetry, often accomplished through dimer formation. They contain specific motifs for interacting with DNA, including the helix-turn-helix motif, the zinc finger motif, the leucine zipper motif, and the helix-loop-helix motif. [Reproduced from McKee and McKee 2003. With permission.]

structures in the organism. Mutations in these genes can result in the transformation of one body part into another during development (Figure 3.1.4.B).

Homeobox transcription factors are altered in various malignancies.

• Frequent elevation of hoxA9 gene expression occurs in acute myeloid leukemia (AML).

• The Histone Methyl Transferase MLL is an upstream regulator of hox gene expression through direct promoter binding and Histone modification. Reciprocal rearrangements of the mll (hrx, all-1) gene are most common in infant ALL and secondary AML.

• NUP98-HOX fusion proteins are generated in the chromosome translocation t(7;11)(p15;p15), which is associated primarily with AML (M2 and M4). The chimeric transcription factor acts as an oncogene [Borrow et al. 1996; Nakamura et al. 1996]. The NUP98-HOX fusions consist of the NH2-terminus of NUP98, containing a region of multiple phenylalanine-glycine repeats (FG

repeats) that may act as a transcriptional coactiva-tor through binding to P300/CBP, and the COOH-terminus of HOX, containing the homeodomain.

Zinc Finger Proteins. A number of proteins have regions that fold around a central Zn2+ ion, producing a compact domain from a relatively short length of the polypeptide chain, termed a zinc finger. The C2H2 zinc finger is one of the most common DNA-binding motifs in transcription factors. Each C2H2 finger has the consensus sequence (Y,F)XCXmCX3 (Y,F)X5LX2HX3-4H. The binding of the Zn2+ ion by the two cysteine and two histidine residues folds the relatively short polypeptide sequence into a compact domain, which can insert its a-helix into the major groove of DNA. C2H2 zinc finger proteins generally contain three or more repeating finger units and bind as monomers. Another type of zinc finger structure, designated the C4 zinc finger, is a part of more than 100 transcription factors, including the Steroid Hormone Receptor superfamily. The DNA-binding domain of these proteins has the

Figure 3.I.4.B. Homeobox genes. Conserved pathways of homeotic gene action in leukemo-genesis. The hox genes dictate the body plan during embryogenesis. They are designated hox-A through hox-D and are arranged on four separate chromosomes (four rows of colored squares). Genes within the hox clusters show striking structural and functional conservation, as indicated by the color coding. Most of the hox genes have regulatory roles in normal hematopoiesis. In the model, seven translocation-associated proteins are predicted to regulate hox gene expression. The chimeric oncoproteins involved in leukemogenesis are postulated to act by disrupting the activity of their normal counterparts in hox gene regulation. [Reproduced from Look 1997. With permission.]

consensus sequence CX2CX13CX2CX1415CX5CX9 CX2C. The four critical cysteines in this region bind two Zn2+ ions. C4 zinc finger proteins generally contain two finger units and bind to DNA as homodimers or heterodimers. Homodimers of C4 DNA-binding domains have twofold rotational symmetry and therefore bind to consensus DNA sequences that are inverted repeats. Heterodimeric nuclear receptors do not exhibit rotational symmetry. The zinc finger motif is frequent in DNA-binding domains, but it may also occur in proteins that do not bind to DNA.

• The RB-interacting zinc finger protein RIZ1 (PR-Domain-Containing Protein 2, PRDM2) {1p36} is a tumor suppressor and a member of the Histone/Protein Methyl Transferase superfamily. rizl inactivation is commonly associated with cancer, specifically with colon cancer and melanoma. It occurs through DNA hypermethyla-tion, frameshift mutations, chromosomal deletion, or missense mutations.

• Kruppel-Like Factor 6 (KLF6) {10p15} is a ubiquitous zinc finger tumor suppressor. Up-regulated expression of klf6 reduces cell proliferation and increases the levels of P21WAF1. It is inactivated by loss or mutation in most sporadic colorectal cancers and most colorectal cancers occurring on the basis of inflammatory bowel disease. Chromosome 10p is deleted in 50-60% of prostate cancers, and loss of heterozygosity of klf6, accompanied by mutations in the remaining allele, occur.

• The oncogene znf217 (zinc finger protein 217) encodes alternatively spliced Kruppel-like transcription factors of 1,062 and 1,108 amino acids. Each contains a DNA-binding domain of multiple C2H2 zinc fingers, and a proline-rich transcription activation domain. ZNF217 immortalizes mammary epithelial cells. This is associated with initial telomere erosion, followed by an increase in Telomerase activity and telomere length stabilization [Nonet et al. 2001].

• The chimeric aml 1-evi 1 gene is generated by the t(3;21)(q26;q22) translocation. In AML 1-EVI 1, an NH2-terminal fragment of AML 1, including a RUNT homology domain, is fused to the entire EVI 1 zinc finger protein. AML 1-EVI 1 plays a pivotal role in progression of hematopoietic stem cell malignancies, such as chronic myelocytic leukemia and myelodysplastic syndrome.

Winged-Helix (Forkhead) Proteins. The forkead box family of genes consists of at least 43 members. Winged-helix proteins generally bind to DNA as monomers. The DNA-binding domains in Histone H5 and several transcription factors that function during early development have the winged-helix motif (forkhead motif). The FOXO subgroup of forkhead transcription factors (Figure 3.1.4.C), comprising FOXO 1A (FKHR), FOXO3A

Figure 3.1.4.C. Structure of FOXO transcription factors. FOXO transcription factors are regulated by phosphorylation and acetylation in response to Insulin, growth factors, and stress stimuli. FOXO posttranslational modifications alter the subcellular localization of these transcription factors and affect FOXO degradation, DNA-binding ability, transcriptional activity, or protein-protein interactions. Sites that are conserved in FOXO members but that have not yet been confirmed to be modified in a particular family member are italicized. PKB sites are shown in black, SGK (Serum and Glucocorticoid Inducible Kinase) are black, sites for IKKP (I-kB Kinase P) are orange, sites for JNK (JUN N-Terminal Kinase) are green, DYRK (Dual Specificity Tyrosine Phosphorylation-Regulated Kinase) sites are red, sites for CK1 (Casein Kinase 1) phosphorylation are purple, and acetylation sites are blue. FH = forkhead domain, NLS = nuclear localization signal, NES = nuclear export sequence. [Reproduced from Greer and Brunet 2005. With permission from Macmillan.]

Figure 3.1.4.C. Structure of FOXO transcription factors. FOXO transcription factors are regulated by phosphorylation and acetylation in response to Insulin, growth factors, and stress stimuli. FOXO posttranslational modifications alter the subcellular localization of these transcription factors and affect FOXO degradation, DNA-binding ability, transcriptional activity, or protein-protein interactions. Sites that are conserved in FOXO members but that have not yet been confirmed to be modified in a particular family member are italicized. PKB sites are shown in black, SGK (Serum and Glucocorticoid Inducible Kinase) are black, sites for IKKP (I-kB Kinase P) are orange, sites for JNK (JUN N-Terminal Kinase) are green, DYRK (Dual Specificity Tyrosine Phosphorylation-Regulated Kinase) sites are red, sites for CK1 (Casein Kinase 1) phosphorylation are purple, and acetylation sites are blue. FH = forkhead domain, NLS = nuclear localization signal, NES = nuclear export sequence. [Reproduced from Greer and Brunet 2005. With permission from Macmillan.]

(FKHRL1), and FOXO4 (AFX), mediates cellular responses that include glucose metabolism, stress responses, cell cycle regulation, and apoptosis. The FOXO factors all function as transcriptional activators and bind as monomers to the consensus DNA sequence TTGTTTAC. FOXO activity is regulated by various growth pathways:

- At rest, FOXO transcription factors are acety-lated. Their deacetylation promotes cell cycle arrest and quiescence.

- Activation of the small GTPase RAS regulates FOXO activity through a mechanism that involves the RAL GTPase. Upon mitogenic signaling, RAS associates with and activates several GEFs for RAL (RAL-GEFs). In response to physiologic stimuli, this causes FOXO activation. However, the activation of RAL by oncogenic RAS mediates FOXO4 phosphorylation on threonine 447 and threonine 451, which are located within the COOH-terminal transac-tivation domain, and suppresses its transcrip-tional activity.

- FOXO transcription factors are targets of Phosphatidylinositol 3-Kinase^PKB signaling. PKB directly phosphorylates FOXO members on threonine 32, serine 253, and serines 315, leading to their nuclear export and inhibition of FOXO-dependent transcription. This is due to the generation of consensus binding sites for 14-3-3 proteins (RSXpSXP) on FOXO after pho phorylation by PKB. 14-3-3 binding causes the displacement of FOXO from the DNA. FOXO export then proceeds in a manner that requires both 14-3-3 binding and intact FOXO nuclear export sequences. Conversely, the activation of FOXO antagonizes the positive effects of Phosphatidylinositol 3-Kinase on cellular proliferation.

- FOXO family members are substrates for Caseine Kinase-1.

- FOXO3A is a direct target of IKK (I-kB Kinase). Phosphorylation by IKK causes the cellular relo-calization of FOXO3A to the cytoplasm, followed by ubiquitination and degradation in the protea-some pathway.

Forkhead transcription factors may play roles in cancer, with FOXO family members acting as tumor suppressors.

• In glioblastoma, deregulation of the Phos-phatidylinositol 3-Kinase signaling pathway is common. Activation of PKB may be due to the the loss of pten. PKB activity, in turn, is correlated with the phosphorylation of the Forkhead transcription factors FOXO1, FOXO3A, and FOXO4.

• trail is a transcriptional target of FOXO3A (FKHRL1), and cd95l is a transcriptional target for FOXO1A (FKHR). The decreased activity of FOXO3A and FOXO 1A in prostate cancers, resulting from the loss of PTEN, leads to a decrease in TRAIL expression. This may contribute to increased survival of the tumor cells [Modur et al. 2002].

• In chronic myeloid leukemia, BCR-ABL mediates the inhibition of TRAIL and BIM. This occurs through activation of Phosphatidylinositol 3-Kinase and the downstream phosphorylation and inactivation of FOXO3A. FOXO3A activates bim transcription through a FOXO binding site (FHRE) located within the promoter. FOXO3A and BCL-6 jointly repress cyclin D2 transcription through a STAT5/BCL6 site located within the cyclin D2 promoter. BCR-ABL signaling abolishes this effect Fernandez de Mattos et al. 2004; Essafi et al. 2005].

• During myoblast differentiation, Phosphatidylino-sitol 3-Kinase signaling leads to myoblast fusion and activation of the terminal differentiation program. This requires the transient exclusion of FOXO from the nucleus. Unchecked FOXO activity, caused by chromosomal translocations, results in alveolar rhabdomyosarcomata (ARMS). Most of these tumors are caused by the presence of transforming chimeric oncogene products, PAX3-FOXO1 in t(2;13)(q35;q14) or PAX7-FOXO1 in t(1; 13)(p36;q14). These chimeric transcription factors activate PAX responsive genes with 10- to 100fold higher potency than the wild-type PAX proteins.

• In myeloid leukemia, foxo3 and foxo4 can participate in chromosomal translocations with the Trithorax-related transcription factor mll.

• The Forkhead Box m1b (FOXm1b) transcription factor is essential for the development of hepato-cellular carcinoma. In the absence of FOXm1b, resistance to hepatocellular carcinoma development is associated with nuclear accumulation of the cell cycle inhibitor P27KIP1 and reduced expression of the CDK1 activator CDC25B [Kalinichenko et al. 2004].

Helix-Loop-Helix Proteins. The helix-loop-helix proteins contain a NH2-terminal a-helix with basic residues that interact with DNA, a middle loop region, and a COOH-terminal region with hydrophobic amino acids spaced at intervals characteristic of an amphipathic a-helix. Because of the basic amino acids characteristic of this motif, transcription factors containing it are referred to as basic helix-loop-helix (bHLH) proteins. Various helix-loop-helix proteins can form heterodimers, thus extending the range of target sequences. The DNA-binding domain of dimeric helix-loop-helix transcription factors contains a structural motif, in which a nonhelical loop of the polypeptide chain separates two a-helical regions in each monomer.

Notch proteins form transmembrane receptors. After binding to their ligands, two proteolytic cleavages within Notch release the NICD. This fragment translocates to the nucleus where it can interact with inhibitory helix-loop-helix proteins that are bound to DNA. The NICD has a transcriptional activation domain and activates specific genes depending on the cofactor it associates with.

• The tall (scl, tcl5) gene encodes a basic helix-loop-helix transcription factor required for hematopoiesis and vasculogenesis. Aberrant transcriptional activation of tall is a frequent event in T-cell acute lym-phoblastic leukemia (T-ALL). TAL1 can bind the E-boxes in the p16 and the pre-tcra promoters, and functionally suppress the activity of each promoter. This may account for the influence by TAL1 on T-lymphocyte proliferation and differentiation. The overexpression of tall in hematopoietic progenitor cells promotes cell cycle division [Hansson et al. 2003].

• Constitutive expression of the proto-oncogene c-myc results in transformation and contributes to the progression of a wide range of tumors. MYC executes its activities mostly through transcrip-tional repression of cell cycle inhibitors, including gasl, p15, p21, p27, and gadd-34, gadd-45, and gadd-153. This repression occurs through at least two distinct mechanisms.

-MYC-MAX heterodimers bind to the Inr element in their cognate promoters and inhibit MIZ-1 or other transcriptional activators via the COOH-terminal domain of c-MYC. -c-MYC binds to the SP1 transcription factor via the c-MYC central region and inhibits SP1 tran-scriptional activity. The ability of c-MYC to repress the transcription of growth arrest genes may contribute to its potential to promote proliferation and oncogenesis [Gartel and Schors 2003].

• TFE3 {Xp 11.22} binds to the |-E3 motif of the immunoglobulin heavy chain enhancer. It is expressed in many cell types. TFE3 is involved in oncogenic translocations in childhood renal cancers. Common fusion partners include aspscr1, prcc, sfpq, and cltc.

Leucine Zipper Proteins. The leucine zipper transcription factors contain the hydrophobic amino acid leucine at every seventh position in the COOH-terminal portion of their DNA-binding domains. These proteins bind to DNA as dimers. The name leucine zipper denotes the existence of two extended a-helices that grip the DNA molecule at two adjacent major grooves, separated by about half a turn of the double helix. The portions of the a-helices contacting the DNA include basic residues that interact with phosphates in the DNA backbone and additional residues that interact with specific bases in the major groove. In other DNA-binding proteins, the leucines are replaced by different hydrophobic amino acids in the critical positions. Like the leucine zipper proteins, they form dimers containing a COOH-terminal coiled-coil dimeriza-tion region and NH2-terminal DNA-binding domain. The term basic zipper (bZip) refers to all proteins with these common structural features. Many basic zipper transcription factors are heterodimers of distinct polypeptide chains, each containing a basic zipper domain. A large number of bZip transcription factors are resident in the nucleus. They include c-JUN, JUN-B, JUN-D, c-FOS, and FRA.

• The translocation t(12; 16)(q13;p 11) in malignant myxoid liposarcoma causes the fusion of the CHOP-dominant negative transcription factor gene with the nuclear RNA-binding protein TLS (FUS). In TLS-CHOP (Translocation Liposarcoma- CCAAT/Enhancer Binding Protein Homologous Protein), the RNA-binding domain of TLS is replaced by the DNA binding and leucine zipper dimerization domain of CHOP. In myeloid leukemia with the t(16;21) (p11;q22) translocation, ERG is fused with TLS. The NH2-terminal domain of TLS binds to RNA Polymerase II and this binding is retained by the TLS-ERG fusion protein.

• C/EBPs (CCAAT/EBP) are a family of leucine zipper transcription factors. They regulate cellular proliferation and apoptosis in the mammary gland. Multiple forms of C/EBPP are generated by variation in translation via prote-olytic cleavage. Alterations in the ratio of the C/EBPP-LIP (Liver-Enriched Inhibitory Protein) form to the C/EBPP-LAP (Liver-Enriched Activating Protein) form play a role in the development of breast cancer [Zahnow 2002]. • Malignant melanoma of soft parts (MMSP, soft tissue clear cell sarcoma) is a rare and aggressive tumor that mainly develops in tendons and aponeuroses of patients between 15 and 35 years of age, and that may also be derived from neu-roectoderm. In malignant melanoma of soft parts, the translocation t(12;22)(q13;q12) fuses the NH2-terminal domain of EWS {22q12} to the bZIP domain of ATF1 (Activating Transcription Factor 1) {12q13}, a transcription factor that is normally regulated by cAMP [Zucman et al. 1993].

Nuclear receptors. The nuclear receptor superfamily comprises some 50 members, including the Glucocorticosteroid Receptor, Estrogen Receptor, Progesterone Receptor, Testosterone Receptor, Retinoic Acid Receptors, Retinoid Receptors, and PPARs. Nuclear receptors reside in the cytoplasm. Once ligated by steroid hormones that diffuse into the cells, they shuttle to the nucleus and execute their functions as activators or repressors of target genes. These receptors contain domains for ligand binding, for DNA binding, and for transcriptional activation. They can exist as homodimers or heterodimers, with each partner binding to specific response element sequences that exist as half-sites and are separated by variable length nucleotide spacers between direct or inverted half-site repeats.

Enhancers. Enhancers generally range in length from about 50-200 base pairs and include binding sites for multiple transcription factors. The transcription factors that bind to a single enhancer may bind cooperatively, producing a multiprotein complex (enhancosome) on the enhancer DNA. Architectural proteins bind to the minor groove of the DNA, regardless of the sequence and, as a result, bend the DNA molecule sharply. This bending of the enhancer DNA permits the transcription factors to interact properly. The relatively weak interactions among the bound proteins are strengthened by binding of the transcription factors to neighboring sites, which keeps the proteins at very high relative concentration.

Repressors. Transcription is negatively regulated by repressor proteins. There are inhibitory basic zipper and helix-loop-helix proteins that block DNA binding when they dimerize with a partner polypeptide normally capable of binding DNA. When these inhibitory factors are expressed, they repress tran-scriptional activation by the factors with which they interact. Like activators, many repressors have two functional domains: a DNA-binding domain and a repression domain. A variety of amino acid sequences can function as repression domains. Many of these are relatively short (around 20 amino acids) and contain high proportions of hydrophobic residues. Other repression domains contain a high proportion of basic residues. In some cases, repression domains are larger, well-structured protein domains. The diverse structures of repression domains are probably a reflection of distinct molecular mechanisms for regulating transcription [Lodish etal. 1999].

BTB domains (POZ domains) are proteinprotein interaction domains that can form homodimeric or heterodimeric complexes. ZNF145 (PLZF, Promyelocytic Leukemia Zinc Finger Protein) and BCL-6 (ZNF51, LAZ3) are BTB domain containing zinc finger proteins implicated in oncogenesis, as well as in myelopoiesis and lymphopoiesis. ZNF145 may control cell cycle progression by preventing the expression of cell cycle promoters such as cyclin A. ZNF145 interacts with CUL-3, a component of Ubiquitin Ligases. This interaction regulates transcription by controlling the stability of ZNF145 [Furukawa et al. 2003]. The transcriptional repressor ZBTB7 (LRF, Pokemon, FBI-1) {19p 13.3} binds to BCL-6, but not to ZNF145. This interaction occurs in the nucleus and requires both the BTB and zinc finger domains of the two proteins. ZBTB7 can specifically repress the transcription of the tumor suppressor gene arf through direct binding [Maeda et al. 2005]. ZBTB7 is overexpressed in a large number of cancers.

• Retinoids exert their biological functions through the nuclear receptors RAR and RXR. In the absence of ligand, the RXRa ligand-binding site functions as a repression domain. When the same region binds its cognate ligand, 9-cis-retinoic acid, it is converted into an activation domain. In acute promyelocytic leukemia, a chromosomal translocation produces a chimeric protein between RARa and PML. PML-RARa acts as a dominant negative receptor in the leukemic cells, which results in the arrest of cell maturation at the stage of promyelocytes.

• The protein encoded by the Wilms tumor (wt1) gene is a repressor that is expressed preferentially in the developing kidney. Inheritance of mutations in both the maternal and paternal wt1 alleles prevents the synthesis of functional WT1 protein and invariably leads to the development of kidney tumors early in life. The WT1 protein, which has a C2H2 zinc finger DNA-binding domain, represses the transcription of egr-1 without inhibiting binding of the two activators that normally stimulate the expression of this gene.

• Loss of imprinting (LOI) is the most common molecular abnormality in Wilms tumor. Loss of imprinting of igf-2 in Wilms tumor commonly involves altered methylation in the differentially methylated region upstream of the maternal h19 gene, but not mutations of CTCF or its binding site [Cui et al. 2001].

• Loss of imprinting in cancer involves the loss of the normal silencing of a specific parental allele, and can cause the activation of growth-promoting imprinted genes. Loss of imprinting of igf-2 occurs concomi-tantly with microsatellite instability in both, tumor and normal tissue of patients with colorectal cancers. It is linked to increased methylation, specifically at a CpG island that represents a differentially methylated region upstream of the maternal h19 gene, which regulates the silencing of the igf-2 gene. The methylated nucleotides include the recognition site for the chromatin insulator CTCF. When it is unmethylated, CTCF binds specifically to is region, separating igf-2 from its enhancer. In the absence of CTCF binding, the normally silenced allele of igf-2 can be expressed, initiating a growth-promoting signal [Nakagawa et al. 2001].

• ctcf [Lobanenkov et al. 1990] is a single copy gene on chromosome 16q22. The transcription factor CTCF (NeP1) is composed of 11 zinc fingers, ten belonging to the C2H2 class and one belonging to the C2HC class. CTCF binds to a number of important regulatory regions within the 5' non-coding sequence of myc and regulates myc expression. CTCF harbors several autonomous repression domains, including a zinc finger cluster, which silences transcription through binding directly to the corepressor SIN3A and recruiting Histone Deacetylases. Insulator elements, which act as a barrier to prevent neighboring cis-acting elements from regulating a distal gene, mediate their function by CTCF. ctcf is located in a small region of overlap for common chromosomal deletions in sporadic breast and prostate tumors, suggesting that CTCF acts as a tumor suppressor [Filippova etal. 1998].

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