Disease relevance of CCND1

• We report here that CCND1 promoter activation by estrogens in human breast cancer cells is mediated by recruitment of a c-Jun/c-Fos/estrogen receptor alpha complex to the tetradecanoyl phorbol acetate-responsive element of the gene, together with Oct-1 to a site immediately adjacent [1].
• Rearrangement of CCND1 (BCL1/PRAD1) 3' untranslated region in mantle-cell lymphomas and t(11q13)-associated leukemias [2].
• Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types [3].
• To define further the prevalence of such rearrangements, we report here the result of the molecular study of 34 MCL and six t(11q13)-associated leukemias using a set of probes specific to the different parts of the CCND1 transcript [2].
• CCND1 amplifications were associated with the pharyngeal site in primary carcinomas (P < 0.001), whereas amplifications of ZNF217 were less frequent in pharyngeal carcinomas as compared with primary oral and laryngeal carcinomas (P = 0.02) [4].
• Cyclin D1 overexpression is associated with longer survival in colon cancer [5].

Psychiatry related information on CCND1

• Our data indicated an association with alcohol consumption and the CCND1 gene or protein levels, in both esophageal and gastric cancers [6].
• These results suggest that the expression level of cyclin D1 RNA in bone marrow cells is predictive of the phase evolution in CML and may be helpful in treatment decision-making [7].
• Using a spontaneous transplantable murine model of B cell leukemia/lymphoma (BCL1), we have demonstrated the expression of the B7 costimulatory molecules in addition to the previously described Id determinant and class II major histocompatibility antigens [8].

High impact information on CCND1

• The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas [9].
• A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer [10].
• Notably, either inhibiting apoptosis (by exogenously expressing antiapoptotic Bcl family proteins) or enhancing proliferation (via Cyclin D1 or HPV E7 overexpression) does not result in luminal filling, suggesting glandular architecture is resistant to such isolated oncogenic insults [11].
• Interference with cyclin D1 degradation prevents initiation of G1 arrest and renders cells more susceptible to DNA damage, indicating that cyclin D1 degradation is an essential component of the cellular response to genotoxic stress [12].
• Dominant-negative PIKE prevents the NGF enhancement of PI3K and upregulation of cyclin D1 [13].

Chemical compound and disease context of CCND1

• In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer [14].
• Two of 17 carcinomas showing cyclin D1 expression in more than 5% of neoplastic cells, but without gene amplification, were found to harbor single-base substitutions in CCND1 that changed proline 287 into threonine and serine, respectively [15].
• Following up with this cohort of patients for an average of 4.84 years, we found that the CCND1 A870G polymorphism was inversely associated with overall and disease-free survival, particularly among women with late stage or estrogen/progesterone receptor-negative breast cancer [16].
• A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies [17].
• PATIENTS AND METHODS: CCND1 and cdk4 overexpression in 117 breast cancer cases with long-term follow-up were investigated by means of immunohistochemistry and differential polymerase chain reaction (PCR), using formalin-fixed and paraffin-embedded samples, and compared with ER status and mitotic indices [18].

Biological context of CCND1

• To determine if expression of human D-type cyclin genes correlates with the state of cell growth, we examined the level of mRNAs for CCND1 and a related gene, CCND3, in normal human diploid fibroblasts (HDF) [19].
• Cycloheximide partially blocks the induction of CCND1 and CCND3 gene expression by serum, suggesting that both de novo protein synthesis-dependent and -independent pathways contribute to induction [19].
• Our data thus suggest that amplification and increased expression of CCND1 and CCND3 contribute to the loss of cell cycle control in a small fraction of human malignant gliomas [20].
• However, little is known of the order of appearance of different types of genetic aberrations We studied the ERBB2 (Her-2/neu) and CCND1 (cyclin D1) oncogene amplification in flow cytometrically sorted diploid and nondiploid tumor cell populations by fluorescence in situ hybridization (FISH) [21].
• Therefore, we analyzed the relationship between CCND1 genotype and phenotypic expression of VHL disease [22].

Anatomical context of CCND1

• Moreover, the finding that the CCND1 mRNA half-life was greater than 3 hours (normal tissues, 0.5 hours) in three t(11q13)-associated cell lines stresses the importance of posttranscriptional derangement in the activation of CCND1 [2].
• Appropriate CCND1 gene activity is essential for normal development and physiology of the mammary gland, where it is regulated by ovarian steroids through a mechanism(s) that is not fully elucidated [1].
• CCND1 GG was associated with G3 tumors in the oral cavity/pharyngeal (P = 0.011), but not laryngeal, SCC cases [23].
• FISH analysis revealed that cyclin D1 over-expression was caused by t(11;14)(q13;q32) or extra copies of B-cell leukemia/lymphoma-1 (BCL-1/CCND1), and unknown mechanism without them [24].
• These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis [25].

Associations of CCND1 with chemical compounds

• Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors [14].
• The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 muM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells [26].
• A common adenine-to-guanine substitution polymorphism (A870G) in the CCND1 gene results in an altered messenger RNA transcript and a longer-life protein, which are preferentially encoded by the A allele [27].
• We show here a novel role for cyclin D1 in growth regulation of estrogen-responsive tissues by potentiating transcription of estrogen receptor-regulated genes [28].
• Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1 [29].
• This degradation is independent of phosphorylation of cyclin D1 at threonine 286, which is mediated by the glycogen synthase kinase 3beta and mitogen-activated protein kinase pathways as described in previous studies [30].

Physical interactions of CCND1

• Both in vivo and in vitro, the abundance of assembled cdk4/cyclin D complex increases directly with increasing inhibitor levels [31].
• In contrast, amino-terminal sequences were identified, including the PSTAIRE region, that are important for cyclin D1 binding but are not involved in p16 binding [32].
• A proposed mechanism is p21 sequestration into cyclin D1.Cdk4/6 complexes driven by estrogen-induced transcriptional activation of cyclin D1 gene expression [33].
• Deletion of the N-terminal cyclin D1 binding site severely compromised AR activity (due to loss of FxxLF) but unmasked a repressor action through interaction with the AR C terminus [34].
• Using immunoprecipitation with the anti-cyclin D anti-body, cyclin D can be found in a complex with Cdc2 in suspension-cultured tobacco BY-2 cells [35].

Enzymatic interactions of CCND1

• Expression of wild-type PTEN but not of mutant forms unable to dephosphorylate phosphoinositides reduced the expression of cyclin D1 [36].
• Transduction of BT-474 cells with an adenovirus-encoding active (myristoylated) Akt (Myr-Akt), but not with a beta-galactosidase control adenovirus, prevented the Herceptin- or LY294002-induced down-regulation of cyclin D1 and of phosphorylated GSK-3beta and prevented the accumulation of p27 in the nucleus and cytosol [37].
• Under these same conditions, phosphorylated c-Myc was rapidly down-regulated (by 4 h), while the levels of cyclin D1 and phosphorylated p38 were constant [38].

Regulatory relationships of CCND1

• Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells [39].
• Cyclin D1 is frequently amplified in breast cancer and can activate ER through direct binding [29].
• On laminin, endothelial cells fail to translate Cyclin D1 mRNA and activate CDK4 and CDK6 [40].
• We found that E2F1 overexpression leads to an inhibition of cyclin D1-dependent kinase activity and induces the expression of a p16-related transcript [41].
• Cyclin-dependent kinase 6 (CDK6) binds to and is activated by cyclin D1 and thereby enhances the transition of cells through the G1 phase of the cell cycle [42].

Other interactions of CCND1

• Introduction of cyclin D2 and Rb into the Rb-deficient cell line SAOS-2 led to overt Rb hyperphosphorylation, whereas Rb, expressed alone or together with cyclin D1, remained unphosphorylated [43].
• A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 [44].
• Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively [39].
• Altogether, these results indicate that down-regulation of cyclin D1 is necessary for PCNA relocation and repair DNA synthesis as well as for the start of DNA replication [45].
• Coexpression of cyclin D1 with its primary catalytic subunit, Cdk4, or with Cdk2, also prevented repair [45].
• This finding represents the first evidence that cyclin D1 is targeted by beta-TrCP [46].

Analytical, diagnostic and therapeutic context of CCND1

• To investigate whether CCND1 genotype influences risk for colorectal adenoma, we genotyped CCND1 by PCR/RFLP on 161 incident sporadic adenoma cases and 213 controls ages 30-74 years in a North Carolina colonoscopy-based case-control study [47].
• Immunohistochemistry revealed CCND1 to be negative in all lymphomas [48].
• CCND1 amplification was found in 38% of the cell lines by Southern blot analysis [49].
• Northern blot analysis of CCND1 expression showed a relative overexpression in 16 of 23 neuroblastoma cell lines and 10 of 15 tumor samples [50].
• External imaging of CCND1 cancer gene activity in experimental human breast cancer xenografts with 99mTc-peptide-peptide nucleic acid-peptide chimeras [51].

References