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Minireview: Cyclin D1: Normal and Abnormal Functions

Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057-1468

Address all correspondence and requests for reprints to: Richard G. Pestell, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, 3970 Reservoir Road NW, Box 571468, Washington, DC 20057-1468. E-mail: pestell{at}georgetown.edu.

Abstract

Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G₁-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.

FOR ENDOCRINOLOGISTS AND oncologists, discoveries in the field of cell-cycle regulation have provided key new insights that now impact clinical care. The importance of this field was highlighted through prominent recognition when the Nobel Prize in physiology or medicine was awarded to Hartwell, Nurse, and Hunt in 2001. Since the initial discovery of cdc2 [cyclin-dependent kinase (CDK)1] in yeast, now more than 13 CDKs and 25 proteins with homology in the cyclin box have been identified in the human genome (1). These CDKs heterodimerize with distinct regulatory subunits referred to as cyclins. Among these regulatory subunits, the cyclin D1 gene product has become particularly well known for its prominent role in driving tumorigenesis.

The human cyclin D1 gene was initially cloned as a break point rearrangement in parathyroid adenoma (2) (Fig. 1). In parallel, the murine cyclin D1 homologue was identified as a colony-stimulating factor-1-responsive gene in macrophages (3). It is now known that cyclin D1, when targeted to the parathyroid gland, is sufficient to induce parathyroid adenoma in transgenic mice and regulates Ca⁺⁺ sensing (4). In macrophages, cyclin D1 is essential for colony-stimulating factor-1-mediated guided migration (5). Over the last 13 yr, an understanding of cyclin D1 activity has helped to distill the mechanisms governing DNA synthesis in cells, and the molecular mechanisms driving tumorigenesis. In the last 5 yr, our understanding of the mechanisms by which cyclins regulate proliferation and differentiation has evolved (6, 7, 8). This minireview will focus on the surprising new discoveries of the CDK-independent function of cyclin D1 and the importance of cyclin D1 to endocrinology and metabolism.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Structure of cyclin D1. Schematic representation of genomic structure of Cyclin D1 gene (A), functional domains of cyclin D1 protein (B), and alternative splicing of cyclin D1 (C). Cyclin D1 sequence derived from intron 4 is shown in blue.

Several findings are consistent with a model in which cyclin D1 serves as a key sensor and integrator of extracellular signals of cells in early to mid-G₁ phase, mediating its function through binding both the CDKs and histone acetylase [p300/cAMP response element-binding protein-binding protein (CBP) and P/CAF] and histone deacetylases to modulate local chromatin structure of the genes that are involved in regulation of cell proliferation and differentiation. The abundance of cyclin D1 is induced by growth factors including epithelial growth factor and IGF-I (9) and IGF-II (10); amino acids (11); lysophosphatidic acid (12); and hormones including androgens (13), retinoic acid (14), and peroxisome proliferator-activated receptor (PPAR) ligand (15); secreted factors from adipocytes (16) and gastrointestinal hormones such as gastrin each regulate cyclin D1 expression in specific cell types (17, 18). TGFß and PTHrP regulate cyclin D1 in chondrocytes (19), and endostatin caused G₁ arrest of endothelial cells through inhibition of cyclin D1 (20). Many oncogenic signals induce cyclin D1 expression and do so through distinct DNA sequences in the cyclin D1 promoter including Ras (21); Src (22); ErbB2 (23); ß-catenin (24, 25); oncogenic signal transducer and activator of transcriptions (STATs) (26, 27, 28); and simian virus 40 small t antigen, a particularly crucial oncogene in transformation of human cells (29).

Cyclin D1 is the regulatory subunit of the holoenzymes that phosphorylate and, together with sequential phosphorylation by cyclin E/CDK2, inactivate the cell-cycle inhibiting function of the retinoblastoma protein (pRb). pRb serves as a gatekeeper of the G₁ phase, and passage through the restriction point leads to DNA synthesis (30, 31) (Fig. 2). Overexpression of cyclin D1 is known to correlate with the early onset of cancer and risk of tumor progression and metastasis (6, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). However, a number of studies have shown a surprising lack of correlation between increased cyclin D1 expression and increased DNA synthesis in tumors (43, 44).

View larger version (27K): [in this window] [in a new window]   FIG. 2. Summary of cyclin D1 function. A, Schematic representation of pRb phosphorylation by G1 phase cyclins, cyclin D1 and cyclin E. Biochemical functions (B) and biological functions (C) of cyclin D1 are summarized. TF, Transcriptional factor.

In addition to its CDK-binding function, a body of evidence now indicates that D-type cyclins have CDK-independent properties (6, 49, 50). As previously proposed (50), the role of these properties in cellular growth, metabolism, and cellular differentiation are substantial. Cyclin D1 forms physical associations with more than 30 transcription factors or transcriptional coregulators (6, 51, 52, 53). Several nuclear receptors, including the androgen receptor (AR), estrogen receptor (ER) , thyroid hormone receptor, and PPAR, bind directly to cyclin D1 within cultured cells. Both basal and ligand-dependent transactivation of nuclear receptors is regulated by cyclin D1 (15, 54, 55, 56, 57, 58, 59, 60, 61). Cyclin D1 associates with p300/CBP-associated factor (P/CAF) and potentiates activation of ER (62), whereas cyclin D1 represses AR hormone-dependent signaling in a P/CAF-dependent manner (55). Recent studies of microarray data from tumors overexpressing cyclin D1 identified CCAAT/enhancer binding protein (C/EBP) ß as a target of cyclin D1 (63). There is evidence that cyclin D1 associates with the TATA-box binding protein-associated factor (II)250 and suppresses pRb-mediated inhibition of TATA-box binding protein-associated factor (II)250 kinase activity (64, 65). Deletion of the N-terminal 20 amino acids of cyclin D1 impaired pRb kinase activity but did not affect its transforming ability (6, 66), suggesting domains other than those involved in pRb inactivation may contribute to the transforming function of cyclin D1.

Cyclin D1 and Cancer

Genetic aberrations in the regulatory circuits that govern transit through the G₁ phase of the cell cycle occur frequently in human cancer, and overexpression of cyclin D1 is one of the most commonly observed alterations (40). One model suggests that the overexpression of cyclin D1 may serve as a drive oncogene through its cell-cycle regulating function. Cyclin D1 is amplified and/or overexpressed in a substantial proportion of different human tumors. Increased cyclin D1 abundance occurs relatively early during tumorigenesis (67). Cyclin D1 was initially cloned and recognized as an oncogene in the development of parathyroid tumors (2, 68, 69). A subset of parathyroid adenomas contains a clonal rearrangement that juxtaposed the promoter of the PTH gene in proximity to the cyclin D1 oncogene, resulting in overexpression of cyclin D1 (2, 69). It was subsequently demonstrated that 20–40% of parathyroid adenomas overexpress the cyclin D1 protein (4, 68, 70, 71, 72, 73). Overexpression of cyclin D1 protein is not limited to neoplastic proliferation of parathyroid tissue but is also seen in nonneoplastic proliferation of parathyroid gland. However, cyclin D1 protein expression was rarely present in normal parathyroid tissue (71). Transgenic animal models with parathyroid-targeted overexpression of the cyclin D1 oncogene have further confirmed the role of cyclin D1 in driving abnormal parathyroid cell proliferation. Intriguingly, the PTH–cyclin D1 transgenic mice not only developed abnormal growth of parathyroid cells but also developed hyperparathyroidism (4). Thus, cyclin D1 may not only control cellular proliferation but also contributes to abnormal hormonal secretion. However, the molecular mechanism for cyclin D1 in regulating PTH secretion remains to be determined.

The cyclin D1 gene, CCND1, is amplified in 15% and overexpressed in 30–50% of primary human breast cancers. In most cancer types, including lung, breast, sarcoma, and colon cancer, cyclin D1 overexpression results from induction by oncogenic signals, rather than a clonal somatic mutation or rearrangement in the cyclin D1 gene (74).

A common A/G single nucleotide polymorphism (A870G) within entron 4 of the cyclin D1 gene results in two distinct mRNA transcripts (isoforms a and b). The alternately spliced RNA transcripts (isoform b) encodes a protein in which the last 55 amino acids of the C terminus of cyclin D1 are replaced by a shorter sequence encoded by intron 4 (75, 76) (Fig. 1C). This truncated form of cyclin D1 has been linked to higher incidence of tumor onset including lung cancer, colon cancer, and other cancer types (77, 78, 79, 80). Given the surprisingly distinct function of these two isoforms when expressed in cultured cells (81, 82), identification of the proteins binding these distinct C termini will be of interest.

Investigation of the biological function of cyclin D1, and the related cyclin E, using transgenic species revealed surprising redundancy of these genes for normal development and cell cycle progression. Cyclin D1-deficient mice displayed retinal apoptosis, failed terminal alveolar breast bud development in response to pregnancy, altered fat metabolism with hepatic steatosis, and defects in macrophage cellular migration (5, 15, 83, 84). Cyclin D1^–/– mouse embryo fibroblasts (MEFs) showed increased apoptosis on several substrates and enhanced UV-induced cell death (9). Cyclin E expression rescued the mammary gland and retinal developmental abnormalities in only approximately 30% of cyclin D1^–/– mice, suggesting cyclin D1-specific function in these tissues. Intriguingly, p27^KIP1 (cyclin-dependent kinase inhibitor 1B) deficiency also rescued the mammary gland and retinal defects of cyclin D1-deficient mice, suggesting that p27^KIP1 may be negatively regulated by cyclin D1 (85, 86). Inactivation of cyclin E /CDK2 in mice also resulted in only focal abnormalities. Cyclin E1/E2 knockout mice have defects in spermatogenesis and trophoblast giant cell formation (87), cell types that require repeated rounds of endoreduplication (rounds of S phase without cell division) (88). CDK2^–/– mice exhibited defects in spermatogenesis and female gametogenesis (89). Although cell cycle transition was normal in cyclin E^–/– MEFs, the prereplication complexes, which form at origins of DNA replication, were defective, consistent with a role for cyclin E kinase in facilitating minichromosome maintenance complex loading (88). Thus, genetic deletion of the G₁ phase regulatory cyclins suggests an unanticipated but important role for cyclin D1 in cellular differentiation, metabolism, and cellular migration and a role for cyclin E in facilitating minichromosome maintenance association with chromatin.

Tissue culture-based experiments evidenced cyclin D1 functions as a collaborative oncogene that enhances oncogenic transformation of other oncogenes (i.e. Ras, Src, E1A) in cultured cells (22, 90, 91, 92). Targeted expression of cyclin D1 or cyclin E induced mammary tumors (93, 94). Collaborative oncogenesis was also shown in vivo as Eµ-cyclin D1-induced lymphomagenesis was enhanced in rate of onset and progression when mated with Eµ-Myc transgenic mice (95). Conversely, cyclin D1^–/– mice were resistant to mammary tumorigenesis induced by either ErbB2 or Ras (96), consistent with earlier studies using cyclin D1 antisense (23). The role of cyclin D1 seems to be tissue and oncogene specific. Cyclin D1-deficient mice showed enhanced mammary tumorigenesis in response to activation of the ß-catenin signaling pathway (97) but were resistant to gastrointestinal tumor induction by mutation of the Apc^Min gene (98). The possibility that these differences in tissue and oncogene-dependent function of cyclin D1 may relate to a role for cyclin D1 in tissue progenitor cell number is being examined by several groups. Recent studies suggest that cyclin D1 may be a potential therapeutic target in gastrointestinal malignancy (1) because transgenic mice with reduced cyclin D1 expression have reduced predisposition to gastrointestinal tumorigenesis (98).

Cyclin D1 Regulation of Nuclear Hormone Receptor

Cyclin D1 is a positive regulator of ER-mediated transcription (58, 59, 60, 62, 99). Cyclin D1 enhances transcription of estrogen response element-responsive genes, independent of CDK-binding activity. Unliganded ER binds to cyclin D1 in vivo and in vitro. ER activation by cyclin D1 is not inhibited by antiestrogens (99). Cyclin D1 increases the transcriptional activity of ER through increased binding of both liganded and unliganded receptor to estrogen response element sequences and increases association of ER with P/CAF (99). P/CAF in turn potentiates cyclin D1 ER activity, and this effect is largely dependent on the acetyltransferase activity of P/CAF. Together these finding suggest a model in which cyclin D1 triggers ER activation through the recruitment of P/CAF (58, 62, 99). Cyclin D1 overexpression correlates with a favorable clinical outcome and better response to tamoxifen in ER-positive human breast cancers (100, 101).

Cyclin D1 selectively inhibits ligand-dependent AR function in several cell types, including breast cancer, bladder cancer, and androgen-independent prostate adenocarcinoma cell lines (54, 55, 56, 57). Cyclin D1 forms a specific complex with the AR, requiring the C terminus of cyclin D1 (55). The mechanism by which cyclin D1 inhibits liganded AR appears to be in part dependent on HDACs or histone acetyltransferases (HATs) (55, 57). In keeping with this observation, p300 through its HAT domain and P/CAF, rescued cyclin D1-mediated AR transrepression (55). Both cyclin D1 and the AR bind to similar domains of P/CAF, and cyclin D1 displaced binding of the AR to P/CAF in vitro (55). Together, these studies suggest cyclin D1 binding to the AR may repress ligand-dependent AR activity by competing for AR coactivators or through recruitment of AR corepressors with HDAC activity.

Cyclin D1 Regulates Adipogenic Transcription Factors and Adipogenesis

The transcription program that coordinates cellular differentiation of adipocytes has been mapped in vitro and in vivo (reviewed in Ref. 102). PPAR is a ligand-activated transcription factor, which is selectively induced by ligands of the thiazolidinedione class. PPAR plays a critical role in fatty acid metabolism, energy homeostasis, and adipogenesis (61, 103). A second transcription factor playing a key role in adipogenesis is C/EBP. C/EBPß functions upstream of PPAR in this differentiation cascade (Fig. 3). Two recent studies suggest cyclin D1 may inhibit this differentiation pathway because cyclin D1 was capable of inhibiting the transactivation of C/EBPß (63, 104) or transactivation and function of PPAR (15).

View larger version (19K): [in this window] [in a new window]   FIG. 3. Molecular pathways that are involved in adipocyte differentiation. Cyclin D1 blocks adipocyte differentiation by antagonizing the function of C/EBPß and PPAR.

View larger version (46K): [in this window] [in a new window]   FIG. 4. Ribbon model of cyclin D1 HLH region binding to PPAR. PPAR (gray, with helix 12 in magenta and coactivator binding region of PPAR in green), and cyclin D1 hydrophobic cluster of HLH motif colored red. (The position alignment, determined by energy minimization using the AMBER force field, displays the cyclin D1 HLH motif in an alignment similar to that of a nuclear receptor corepressor.) [Reproduced with permission from C. Wang et al.: Mol Cell Biol 23:6159–6173, 2003 (15 ). © American Society for Microbiology.]

Cyclin D1 and myogenic differentiation
Differentiation of skeletal myoblasts is controlled by the basic HLH (bHLH) regulators (105, 106, 107, 108). Activation of muscle gene transcription in differentiating skeletal myoblasts requires their withdrawal from the cell cycle. Ectopic expression of cyclin D1 inhibited transcriptional activation of muscle gene reporter constructs by myogenic bHLH regulators, and this effect was dependent on the carboxy terminal but not the pRb binding motif of cyclin D1 (109). It has been proposed that G₁ cyclin-CDK activity blocks the initiation of skeletal muscle differentiation by both pRb-dependent and pRb-independent mechanisms (110). Cyclin D1 may also regulate myoblast differentiation by interfering with the MyoD-CDK4 interaction, which normally disrupts the ability of MyoD to induce myogenesis (51).

Cyclin D1, BETA2/NeuroD, and enteroendocrine cell differentiation
The mammalian small intestinal epithelium undergoes continuous self-renewal and differentiation along the crypt-villus axis. Cellular proliferation is restricted to the crypt compartment, whereas expression of the hormone secretin in enteroendocrine cells is restricted to the nondividing villus compartment of the intestine. The bHLH protein, BETA2/NeuroD, induces cell cycle withdrawal in addition to increasing secretin gene expression (111, 112). Cyclin D1 represses BETA2/NeuroD-dependent transcription of the secretin gene in a CDK4-independent manner. Experiment data suggested that cyclin D1 does not appear to interact directly with BETA2 but instead associates with the C- terminal domain of the transcriptional coactivator p300, which functions as a scaffold to recruit cyclin D1 on BETA2-containing complexes (112).

Repression of STAT3 by Cyclin D1

STAT3 transcription factors are important transcriptional regulators in the Janus kinase 1/STAT pathways, which are activated by various growth factors and cytokines such as epidermal growth factor and IL-6. Binding of these cytokines to their receptors activates the Janus kinase tyrosine kinases, followed by tyrosine phosphorylation of the receptors. This leads to activation and homo- or heterodimerization and translocation of the STAT1/3 transcription factors into the nucleus in which the downstream target genes are activated (113, 114). Cyclin D1 is an important target of the STAT signaling pathway in several cell types (26, 28, 115, 116, 117, 118). Recent studies demonstrated that cyclin D1 inhibits STAT3 activation (114). In coimmunoprecipitation and pull-down assays, cyclin D1 was found to associate with the activation domain of STAT3 upon IL-6 stimulation. Overexpression of cyclin D1 inhibited transcriptional activation by STAT3 proteins, and this effect was again independent of CDK4 kinase activity (114). It was hypothesized that binding of cyclin D1 with the activation domain of STAT3 could occlude the interactions of STAT3 with the RNA polymerase II transcriptional machinery or with its essential cofactors such as CBP/p300; alternatively, STAT3 nuclear localization could be regulated by cyclin D1 in a cell-cycle-dependent manner (114).

Regulation of B-Myb Activity by Cyclin D1

B-Myb, a conserved member of the Myb transcription factor family, plays a role in the G₁/S transition of the cell cycle. Constitutive expression of a human B-myb cDNA in BALB/c 3T3 fibroblasts reduced its growth factor requirements and induced a transformed phenotype (119). Evidence obtained during recent years suggests that cyclin D1, in contrast to cyclin A, inhibits the activity of B-Myb through formation of a B-Myb-cyclin D1 complex (52). Cyclin D1 associates with the central domain of B-Myb in vitro and in cultured cells. The cyclin D1 inhibitory effect on B-Myb was CDK-independent (52). The transcriptional activity of another Myb-like protein, DMP1, is also antagonized by D-type cyclins through a CDK-independent mechanism (53).

Cyclin D1 and HAT

Cyclin D1 associates with HATs, HDACs, and chromatin remodeling proteins. p300 and P/CAF are transcriptional coactivators that contain intrinsic HAT enzyme activities. They are components of a complex of multiple proteins that participate in transcription by supplying HAT activity and linking the general transcriptional machinery to specific activator-responsive promoters. Cyclin D1 physically interacts with p300/CBP and P/CAF (55, 62). Consistent with these findings, the abundance of cyclin D1 affects local histone acetylation and methylation of specific promoters in chromatin immunoprecipitation assays (98). P/CAF and p300 directly associate with cyclin D1 in culture cells (112) and can be recruited into a complex with the ER (62) or AR (55) by cyclin D1. Zwijsen et al. (99) reported an interaction between cyclin D1 and the coactivators SRC1 (steroid receptor coactivator-1) and AIB1 (amplified in breast cancer 1) and showed that cyclin D1 could bring about an estrogen-independent recruitment of SRC1 to the ER.

Cyclin D1 repressed p300 activity in cultured cells in a trichostatin A-dependent manner, suggesting that HDACs are involved in p300 repression (Fu, M., and R. G. Pestell, unpublished data). In line with this observation, cyclin D1 repressed thyroid hormone receptor (TR) by recruiting HDAC3 to form ternary complexes (120). Although cyclin D1 abundance regulates histone acetylation in the context of local chromatin at specific promoter sites (98), it remains to be determined whether cyclin D1 directly affects the enzyme activities of histone acetylase or HDACs (Fig. 5).

View larger version (23K): [in this window] [in a new window]   FIG. 5. Proposed model of cyclin D1 regulation of chromatin structures. Acetylation of histone lysine tails by HATs leads to an open chromatin structure, making DNA more accessible to the transcriptional machinery (125 ). Cyclin D1 physically associates with both P/CAF (55 62 ) and HDACs. Recruitment of HDACs by cyclin D1 is predicted to result in deacetylation of the histone lysine tails and reduce acetylated H4 in the context of the local chromatin structure of specific target genes as recently shown (98 ). Formation of a compacted chromatin structure is predicted to be regulated through cyclin D1 at specific promoters. [Reproduced with permission from G. Felsenfeld and M. Groudine: Nature 421:448–453, 2003 (125 ). © Nature Publishing Group.]

Cyclin D1, Cellular Adhesion, and Mobility

Integrin-mediated cell adhesion to the extracellular matrix, which is required for normal cell growth, transduced at least in part through cyclin D1 via focal adhesion kinase and integrin-linked kinase (ILK). Integrin signaling through focal adhesion kinase regulates cell cycle progression and cyclin D1 abundance at the transcriptional level dependent on integrin-mediated cell adhesion and ERK signaling (122). Cyclin D1 is also induced by the ankyrin repeat containing serine-threonine protein kinase, ILK (123), which elevates cyclin D1 protein levels and transcription through the PI3 kinase and AKT/PKB pathway. Wnt-1 induces both ILK and cyclin D1 mRNA, consistent with a growing evidence that both mitogen signaling and cytoskeletal integrity are required for cell cycle progression through cyclin D1 (124).

Cyclin D1 is essential in cellular adhesion, motility, and guided migration of primary bone marrow macrophages (5). Compared with cyclin D1 wild-type macrophages, cyclin D1^–/– macrophages are constitutively well spread and attached, yielding a flattened, circular morphology with reduced membrane ruffles. The attachment is mediated via increased numbers of circumferentially arrayed focal complexes rich in phospho-Y118 paxillin. The circumferential arrangement of the adhesion sites in the cyclin D1-deficient cells is associated with a closely aligned distribution of multiple cortical F-actin cables. Migration in response to wounding, cytokine-mediated chemotaxis, and transendothelial cell migration of cyclin D1^–/– bone marrow-derived macrophages were all substantially reduced (5). The fact that cyclin D1 abundance regulates the dynamics of cellular adhesion suggest that cyclin D1 may also contribute to cellular growth properties through regulating cellular substratum interactions and therefore contribute to the invasiveness and/or metastatic phenotype, independently of its effects on cell cycle progression (5).

Conclusions

Growing evidence suggests that cyclin D1 physically associates with transcriptional factors or coactivators including HATs and HDACs to regulate transcription and epigenetic changes. The finding that cyclin D1 null mice have failed differentiation of mammary epithelium and hepatic steatosis is consistent with a role for cyclin D1 as a regulator of cellular differentiation and metabolism. Understanding the mechanisms by which cyclin D1 abundance couples the metabolic environment to regulate fat cell formation and metabolism in vivo may provide important insight into the role of metabolism in human cancer.

Acknowledgments

We apologize to the investigators whose work was not cited due to space limitations.

Footnotes

This work was supported by National Institutes of Health (NIH) Grants R01 CA70896, R01 CA75503, R01 CA86072, and R01 CA93596-01 (to R.G.P.) and National Institute of Diabetes and Digestive and Kidney Diseases Grants 1-R21 DK065220-02 (to M.F.). Work conducted at the Lombardi Comprehensive Cancer Center was supported by the Cancer Center Core NIH Grant P30 CA51008-13.

Abbreviations: AR, Androgen receptor; bHLH, basic HLH; BRG, Brahma-related gene; CBP, cAMP response element-binding protein-binding protein; CDK, cyclin-dependent kinase; C/EBP, CCAAT-enhancer-binding protein; ER, estrogen receptor; HAT, histone acetyltransferase; HDAC, histone deacetylase; HLH, helix-loop-helix; ILK, integrin-linked kinase; MEF, mouse embryo fibroblast; P/CAF, p300/CBP-associated factor; PPAR, peroxisome proliferator-activated receptor; pRb, retinoblastoma protein; STAT, signal transducer and activator of transcription.

Received July 26, 2004.

Accepted for publication August 13, 2004.

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