Disease relevance of Ccnd1

• Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors [1].
• These included, for cyclin D1(-/-) mice, body weight, early lethality, retinal hypoplasia, and male aggressiveness and, for p27(-/-) mice, body weight, retinal hyperplasia, and embryo implantation. p27(-/-) traits that were not corrected were the aberrant estrus cycles, luteal cell proliferation, and susceptibility to pituitary tumors [2].
• Consistent with this situation null mutations in the genes for cyclin D1 and Cki p27(Kip1) in mice give opposite phenotypes of dwarfism and gigantism [2].
• Mice lacking p53 and one or two alleles of the cyclin D-dependent kinase inhibitor p18(Ink4c) are prone to medulloblastoma development [3].
• The data suggest that proviral insertions near Cyl-1 in mouse lymphomas are functionally equivalent to the BCL1 translocations that activate cyclin D1 expression in human B-cell malignancies [4].

High impact information on Ccnd1

• Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels [5].
• Our results reveal the presence of alternative mechanisms that allow cell cycle progression in a cyclin D-independent fashion [6].
• In contrast, cyclin D-deficient fibroblasts proliferate nearly normally but show increased requirement for mitogenic stimulation in cell cycle re-entry [6].
• IKKalpha and NF-kappaB activation are also required for optimal cyclin D1 induction [7].
• IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development [7].

Chemical compound and disease context of Ccnd1

• Cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by the primary mitogen TCPOBOP and suggests that a direct effect of the mitogen on this cyclin may be responsible for the rapid onset of DNA synthesis observed in TCPOBOP-induced hyperplasia [8].
• Adenoma growth stimulation by the trans-10, cis-12 isomer of conjugated linoleic acid (CLA) is associated with changes in mucosal NF-kappaB and cyclin D1 protein levels in the Min mouse [9].
• Cyclin D1 content increased when lungs underwent compensatory hyperplasia following damage caused by butylated hydroxytoluene administration to mice and in lung tumor extracts as compared with extracts prepared from uninvolved tissue or control lungs [10].
• As targets of estrogen, cyclin D1, and erbB2 signaling, these candidates offer insights into the nature of the second events involved in breast cancer progression, regulatory events contributing to invasion, and potential targets of combined inhibition of hormone and growth factor signaling pathways [11].
• Transgenic (TG) mice with cyclin D1 overexpression targeted to the oral-esophageal tissue by the EBV ED-L2 promoter showed increased severity in esophageal dysplasia without cancer development, after multiple doses of N-nitrosomethylbenzylamine (NMBA) [12].

Biological context of Ccnd1

• Furthermore, these mice had a 24-hour lag in the hepatic expression of the G(1)/S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1beta cytokine gene [13].
• Gene amplification occurred without overexpression since only one of five tumors with amplification and one of six tumors without Ccnd1 amplification expressed increased protein [14].
• In turn, the ability of cyclin D-dependent kinases to trigger phosphorylation of the retinoblastoma (Rb) protein in the mid- to late G1 phase of the cell cycle makes the inactivation of Rb's growth suppressive function a mitogen-dependent step [15].
• Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway [15].
• Moreover, artificial elevation of cyclin D1 levels is sufficient to induce apoptosis, even in non-neural cell types [16].

Anatomical context of Ccnd1

• In mouse fibroblasts, p27 is associated predominantly with cyclin D1-Cdk4 [17].
• In contrast, all three cyclin D mRNAs are present in the cultures derived from 5-day-old hippocampi, when developmental neurogenesis in the dentate gyrus takes place [18].
• Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation [19].
• In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells [1].
• Moreover, when it is ectopically overexpressed in mammalian cells, cyclin D1 (T156A) assembles with CDK4 in the cytoplasm but is not imported into the cell nucleus [20].

Associations of Ccnd1 with chemical compounds

• Inhibition of Mek1 or phosphoinositide 3-kinase markedly inhibited cyclin D1 expression and replication [21].
• Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner [22].
• Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis [23].
• Proliferation-independent induction of macrophage cyclin D2, and repression of cyclin D1, by lipopolysaccharide [24].
• Results showed that a single administration of TCPOBOP caused a very rapid increase in the levels of cyclin D1, a G1 protein, when compared with two thirds PH (8 hours versus 30 hours) [8].

Physical interactions of Ccnd1

• Cyclin D mutants defective in binding to the retinoblastoma protein were impaired in rescuing mitogenic signaling [25].
• In vivo proliferation of olfactory neuronal lineage cells thus involves functional binding of cyclin D1 with cdk2 and cdk4, with differential activation mechanisms for cdk2 and cdk4 [26].
• Thus Raf mediated growth was associated with elevated p21(Cip1) expression, which may specifically bind with and activate Cdk4/cyclin D complexes and with decreased p27(Kip1) expression [27].
• In addition, cyclin D1/cyclin-dependent kinase (CDK) complex formation increased in the transgenic mice and was correlated with elevated CDK4 and CDK6 kinase activities [28].

Enzymatic interactions of Ccnd1

• Cyclin D-dependent kinases phosphorylate the retinoblastoma (Rb) protein and play a critical role in neuronal cell cycle control and apoptosis [29].
• Analysis on cyclin D1 mutants demonstrated that IKKalpha phosphorylates cyclin D1 at Thr286 [30].
• Concomitantly with the increase in cyclin D2 was a fivefold decrease in cyclin D1 hyper-phosphorylated isoform in mammary glands of pregnant cyclin D2-58 mice [31].

Co-localisations of Ccnd1

• Following activation of the c-fos transgene in vivo and before overt tumor formation, cyclin D1 expression increased dramatically and was colocalized with exogenous c-Fos protein specifically in osteoblasts and chondrocytes, but not in osteoclasts [32].

Regulatory relationships of Ccnd1

• Loss of Rb and Myc activation co-operate to suppress cyclin D1 and contribute to transformation [33].
• Cyclin D1 can also activate the adenovirus E2 promoter via E2F [34].
• Previously we showed that the macrophage-activating agent lipopolysaccharide (LPS) blocks CSF-1-induced proliferation and cyclin D1 expression in macrophages [24].
• CONCLUSION: PTHrP upregulates JunB and reduces cyclin D1 expression while inducing G1 cell cycle arrest in differentiated osteoblasts [35].
• As there is no intervening CpG island, proviral insertions at Fis-1 could influence the expression of Cyl-1 and we describe two virally induced tumours in which this appears to be the case [4].
• Together, these data show that GATA-1 controls growth and polyploidization by regulating cyclin D-Cdk4 kinase activity [36].

Other interactions of Ccnd1

• Analysis of tumor-derived mutations has led to the suggestion that p16INK4a, cyclin D1, cdk4, and the retinoblastoma protein (pRB) are components of a regulatory pathway that is inactivated in most tumor cells [37].
• Most importantly, however, overexpression of the cyclin D-dependent kinase inhibitor p16INK4 protects neurons from apoptotic cell death, demonstrating that activation of endogenous cyclin D1-dependent kinases is essential during neuronal apoptosis [16].
• Induction of cyclin D1 mRNA by CSF-1 was restored in cells forced to express c-myc, and vice versa, suggesting that expression of the two genes is interdependent [25].
• Furthermore, cyclin D1 protein levels were not induced, and the expression of cyclins A, E, and proliferating cell nuclear antigen was delayed [38].
• Cyclin D-dependent kinase activity is required for cell proliferation, yet cyclin D2(-/-) mice have normal levels of mature B-lymphocytes [39].
• AP-1 and CRE double mutants completely abolished the PTHrP effect of cyclin D1 transcription [40].

Analytical, diagnostic and therapeutic context of Ccnd1

• Confocal microscopy analysis revealed cytoplasmic colocalization of cyclin D1 with SSeCKS [41].
• ELISA and/or Northern blot analyses were done to evaluate JunB and cyclin D1 expression [35].
• Immunoprecipitation of cdk2 and cdk4 fractions of protein extracts at 4 days postlesion (mitotic reaction peak) versus control, followed by cyclin D1 immunoblotting, and vice versa, revealed that levels of both cyclin D1/cdk2 and cyclin D1/cdk4 complexes, as well as their kinase activities, were dramatically increased after lesion [26].
• In an effort to understand the role played by the cell cycle control in these processes, expression of cyclin D1, D2, and D3--three major positive regulators of the G1/S transition--has been investigated by in situ hybrization and RT-PCR [42].
• While cyclin D1 expression was mainly found in the cytoplasm of the tumor cells, it shifted to the nucleus in association with cell proliferation after the animals were subjected to a partial hepatectomy (PH), and then returned once more to the cytoplasm when the cells became quiescent [43].

References