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.

The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G 1 /S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G 1 /S-phase cell cycle progression.Loss of heterozygosity of chromosome region 3p21.3 is extremely common in lung, breast, ovarian, nasopharyngeal, and renal tumors (22,27,37,39). Alterations at 3p21.3 are a very early event in primary cancer development, implying the presence of a tumor suppressor gene or genes in this location (20,39). RASSF1 is one of eight predicted genes located in a minimal interval of 3p21.3 as defined by analysis of nested homozygous deletions found in tumor samples (24, 31). Two major splice forms of RASSF1, RASSF1A, and RASSF1C are expressed in normal human epithelial cells that derive from two different promoter regions (5, 6). The resulting mRNAs differ primarily in the selection of the first exon. RASSF1A contains an amino-terminal cysteine-rich region, which is similar to the diacyl glycerol binding domain (C1 domain) found in the protein kinase C family of proteins, and a carboxy-terminal putative Ras-association (RA) domain. RASSF1C is a smaller protein that lacks the amino-terminal C1 domain. Selective epigenetic inactivation of the RASSF1A promoter is an extremely common event in many human cancers. This includes 80 to 100% of SCLC cell lines and tumors (5, 6), 30 to 40% of NSCLC cell lines and tumors (5), 49 to 62% of breast cancers (5, 7), 67 to 70% of primary nasopharyngeal cancers (NPCs) (26), 91% of primary renal cell carcinomas (RCCs), and 100% of RCC lines (10). Ectopic expression of RASSF1A, but not RASSF1C, potently inhibits tumorigenicity of lung cancer cell lines, H1299 and A549 (5, 6), and an RCC line, KRC/Y (10). These results strongly suggest that RASSF1A may function as a tumor suppressor protein in many cells of epithelioid origin; however, the mechanism by which RASSF1A can negatively regulate tumor growth has not been determined.Normal epithelial cells require cell adhesion and the presence of appropriate growth factors to promote cell proliferati...

Modification by acetylation occurs at -amino lysine residues of histones and transcription factors. Unlike phosphorylation, a direct link between transcription factor acetylation and cellular growth or apoptosis has not been established. We show that the nuclear androgen receptor (

Overexpression of c-Myc or E2F1 sensitizes host cells to various types of apoptosis. Here, we found that overexpressed c-Myc or E2F1 induces accumulation of reactive oxygen species (ROS) and thereby enhances serum-deprived apoptosis in NIH3T3 and Saos-2. During serum deprivation, MnSOD mRNA was induced by NF-kappaB in mock-transfected NIH3T3, while this induction was inhibited in NIH3T3 overexpressing c-Myc or E2F1. In these clones, E2F1 inhibited NF-kappaB activity by binding to its subunit p65 in competition with a heterodimeric partner p50. In addition to overexpressed E2F1, endogenous E2F1 released from Rb was also found to inhibit NF-kappaB activity in a cell cycle-dependent manner by using E2F1(+/+) and E2F1(-/-) murine embryonic fibroblasts. These results indicate that E2F1 promotes apoptosis by inhibiting NF-kappaB activity.

Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that is aberrantly activated in many cancer cells. Constitutively activated STAT3 is oncogenic, presumably as a consequence of the genes that it differentially regulates. Activated STAT3 correlated with elevated cyclin D1 protein in primary breast tumors and breast cancer-derived cell lines. Cyclin D1 mRNA levels were increased in primary rat-, mouse-, and human-derived cell lines expressing either the oncogenic variant of STAT3 (STAT3-C) or vSrc, which constitutively phosphorylates STAT3. Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene.