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Cyclin D1 Transcription (cyclin + d1_transcription)
Selected AbstractsCyclin D1 as a Target for the Proliferative Effects of PTH and PTHrP in Early Osteoblastic CellsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2007Nabanita S Datta MS Abstract PTHrP induced a proliferative cyclin D1 activation in low-density osteoblastic cells. The process was PKA and MAPK dependent and involved both AP-1 and CRE sites. In ectopic ossicles generated from implanted bone marrow stromal cells, PTH upregulated cyclin D1 after acute or intermittent anabolic treatment. These data suggest a positive role of PTH and PTHrP in the cell cycle of early osteoblasts. Introduction: The mechanisms underlying the actions of PTH and its related protein (PTHrP) in osteoblast proliferation, differentiation, and bone remodeling remain unclear. The action of PTH or PTHrP on the cell cycle during osteoblast proliferation was studied. Materials and Methods: Mouse calvarial MC3T3-E1 clone 4 cells were synchronized by serum starvation and induced with 100 nM PTHrP for 2,24 h under defined low serum conditions. Western blot, real-time PCR, EMSAs, and promoter/luciferase assays were performed to evaluate cyclin D1 expression. Pharmacological inhibitors were used to determine the relevant signaling pathways. Ectopic ossicles generated from implanted bone marrow stromal cells were treated with acute (a single 8- or 12-h injection) or intermittent anabolic PTH treatment for 7 days, and RNA and histologic analysis were performed. Results: PTHrP upregulated cyclin D1 and CDK1 and decreased p27 expression. Cyclin D1 promoter/luciferase assays showed that the PTHrP regulation involved both activator protein-1 (AP-1) and cyclic AMP response element binding protein (CRE) sites. AP-1 and CRE double mutants completely abolished the PTHrP effect of cyclin D1 transcription. Upregulation of cyclin D1 was found to be protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) dependent in proliferating MC3T3-E1 cells. In vivo expression of cyclin D1 in ectopic ossicles was upregulated after a single 12-h PTH injection or intermittent anabolic PTH treatment for 7 days in early developing ossicles. Conclusions: These data indicate that PTH and PTHrP induce cyclin D1 expression in early osteoblastic cells and their action is developmental stage specific. [source] New concepts regarding focal adhesion kinase promotion of cell migration and proliferationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Braden D. Cox Abstract Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that plays a key role in the regulation of proliferation and migration of normal and tumor cells. FAK associates with integrin receptors and recruits other molecules to the site of this interaction thus forming a signaling complex that transmits signals from the extracellular matrix to the cell cytoskeleton. Crk-associated substrate (CAS) family members appear to play a pivotal role in FAK regulation of cell migration. Cellular Src bound to FAK phosphorylates CAS proteins leading to the recruitment of a Crk family adaptor molecule and activation of a small GTPase and c-Jun N-terminal kinase (JNK) promoting membrane protrusion and cell migration. The relocalization of CAS and signaling through specific CAS family members appears to determine the outcome of this pathway. FAK also plays an important role in regulating cell cycle progression through transcriptional control of the cyclin D1 promoter by the Ets B and Kruppel-like factor 8 (KLF8) transcription factors. FAK regulation of cell cycle progression in tumor cells requires Erk activity, cyclin D1 transcription, and the cyclin-dependent kinase (cdk) inhibitor p27Kip1. The ability of FAK to integrate integrin and growth factor signals resulting in synergistic promotion of cell migration and proliferation, and its potential regulation by nuclear factor kappa B (NF,B) and p53 and a ubiquitously expressed inhibitory protein, suggest that it is remarkable in its capacity to integrate multiple extracellular and intracellular stimuli. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] Blockade of AP-1 activity by dominant-negative TAM67 can abrogate the oncogenic phenotype in latent membrane protein 1-positive human nasopharyngeal carcinomaMOLECULAR CARCINOGENESIS, Issue 11 2007Xin Jin Abstract Although activating protein-1 (AP-1) transcription factors play an important role in mediating metastasis for nasopharyngeal carcinoma (NPC), the biological and physiological functions of AP-1, in relation to the oncogenic phenotype of NPC, are not fully understood. Our previous study showed that the latent membrane protein 1 (LMP1) mediated a primary dimer form of c- jun and jun B. In this study, we used a NPC cell line that express a specific inhibitor of AP-1, a dominant-negative c- jun mutant (TAM67), to investigate the role of AP-1 in regulating the NPC oncogenic phenotype. First, we observed that TAM67 inhibited cell growth in vitro and in vivo. Next, with Western blotting, we discovered that TAM67 impaired the cyclin D1/cdk4 complex but had little effect on the cyclin E/cdk2 complex, concomitantly with inhibiting Rb phosphorylation. RT-PCR and luciferase assay results demonstrated that the levels of cyclin D1 mRNA and the promoter activity in TAM67 transfectants were reduced as compared with control cells. Thereby, we show that blockade of AP-1 transcriptional activity has a negative impact on cyclin D1 transcription. We obtained the first evidence that TAM67 prevented NPC growth both in vitro and in vivo. AP-1 appears to be a novel target for treating or preventing LMP1-positive NPC effectively. © 2007 Wiley-Liss, Inc. [source] Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expressionCANCER SCIENCE, Issue 5 2007Etsu Tashiro Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed. (Cancer Sci 2007; 98: 629,635) [source] Inhibition of NF-,B activation by the histone deacetylase inhibitor 4-Me2N-BAVAH induces an early G1 cell cycle arrest in primary hepatocytesCELL PROLIFERATION, Issue 5 2007P. Papeleu 4-Me2N-BAVAH has been shown to induce histone hyperacetylation and to inhibit proliferation in Friend erythroleukaemia cells in vitro. However, the molecular mechanisms have remained unidentified. Materials and Methods:,In this study, we evaluated the effects of 4-Me2N-BAVAH on proliferation in non-malignant cells, namely epidermal growth factor-stimulated primary rat hepatocytes. Results and Conclusion:,We have found that 4-Me2N-BAVAH inhibits HDAC activity at non-cytotoxic concentrations and prevents cells from responding to the mitogenic stimuli of epidermal growth factor. This results in an early G1 cell cycle arrest that is independent of p21 activity, but instead can be attributed to inhibition of cyclin D1 transcription through a mechanism involving inhibition of nuclear factor-kappaB activation. In addition, 4-Me2N-BAVAH delays the onset of spontaneous apoptosis in primary rat hepatocyte cultures as evidenced by down-regulation of the pro-apoptotic proteins Bid and Bax, and inhibition of caspase-3 activation. [source] | |||||||||||||