CDK Inhibitors in Leukemia and Lymphoma
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
Cyclin D1 is a multifunctional protein that plays a critical role not only as a partner of CDK4/6 (see above) in the regulation of the cell cycle (e.g., the G1/S transition) but also as a transcriptional regulator by modulating the activity of several transcriptional factors (e.g., STAT3) that are CDK-independent. This may explain why cyclin D1 is not only involved in cell cycle progression but also in cell growth and survival (25). Cyclin D1 binds to transcriptional factors STAT3 and NeuroD and inhibits their transcriptional activity, which may be related to the modulation of cell differentiation. Cyclin D1 also interacts with histone deacetylases and, in so doing, blocks access of transcriptional factors to the promoter and inhibits loading of initiation complex (26). Cyclin D1, as an oncogene, also plays an important role in carcinogenesis, probably by driving cells into the S phase and cooperating with various oncogenes (such as Myc and Ras) in malignant transformation. Rearrangement of the cyclin D1 locus and/or overexpression of cyclin D1 have been reported in many human tumors, particularly mantle cell lymphoma (27).
Genetics of liver cancer
J. K. Cowell in Molecular Genetics of Cancer, 2003
Cyclin D1 combines with and activates CDKs to promote cell progression from the G1 to the S phase. It is generally considered to be an oncogene and is overexpressed, as a consequence of gene amplification, in many types of human cancer. Zhang et al. (1993) studied cyclin D1 in HCCs by Southern blotting and immunohistochemistry, and demonstrated amplification and protein overexpression in a small fraction (13%) of these tumors. Furthermore, Nishida et al. (1994) found that cyclin D1 was amplified in 11% of HCCs, and that this was accompanied by mRNA overexpression. Their data also suggest that cyclin D1 amplification is associated with the advanced stages of HCC. Recently, Ito et al. (1999) reported that cyclin D1 overexpression occurred in 32% of HCCs and was significantly associated with poor disease-free survival. In their study, cyclin E overexpression was also detected in 36% of HCCs but was not significantly related to patient outcome.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Alastair G. Stewart in AIRWAY WALL REMODELLING in ASTHMA, 2020
In cell lines that have been constructed to overexpress cyclin D156 or cyclin E,157 the duration of G1 is reduced, the cells are smaller, and there is a diminished requirement for mitogens, indicating the importance of these two cyclins. Microinjection of antibodies against cyclin D1 into fibroblasts overexpressing cyclin D prevented these cells from entering S phase, but these antibodies had no effect when injected near G1/S phase transition.156,158 Cyclin D localises to the nucleus during G1 and disappears from the nucleus as cells proceed into S phase.158 Paradoxically, the acute overexpression of cyclin D1 caused by the microinjection of an expression plasmid into fibroblasts has been shown to prevent entry into S phase.159 This effect may be due to the inhibition of DNA repair in the presence of high levels of cyclin D, which provides an explanation of the difficulty in establishing cell lines with high levels of expression of cyclin D.156
IFN-γ-induced ER stress impairs autophagy and triggers apoptosis in lung cancer cells
Published in OncoImmunology, 2021
Can Fang, Tao Weng, Shaojie Hu, Zhiwei Yuan, Hui Xiong, Bing Huang, Yixin Cai, Lequn Li, Xiangning Fu
Cyclin D1 is a crucial regulator of the cell cycle. IFN-γ significantly reduced cyclin D1 expression, as determined by western blotting (Figure 9a). Interestingly, IFN-γ did not decrease the transcription of CCND1 (Figure 9e). As a similar pattern was observed in LAMP, we speculated that cyclin D1 is also regulated by IFN-γ-induced ER stress. The ER stress inhibitor 4-PBA significantly restored the protein level of cyclin D1 (Figure 9f), suggesting that ER stress is involved in regulating the expression of cyclin D1. Next, we hypothesized that the reduction in cyclin D1 expression was due to ER stress-mediated suppression of protein synthesis. As shown in Figure 9g, GSK2606414 did not restore cyclin D1 expression in IFN-γ-treated cells. Interestingly, MG132 significantly restored cyclin D1 expression in IFN-γ treated cells (Figure 9h). Furthermore, we assessed the degree of cyclin D1 ubiquitination using immunoprecipitation with an anti-cyclin D1 antibody, followed by western blotting with an anti-ubiquitin antibody. As shown in Figure 9i, ubiquitination was detected and significantly increased in IFN-γ treated cells in the presence of MG132 compared to untreated cells. Our data indicate that ER stress-enhanced proteasome activity, but not the PERK-eIF2α-axis, may cause the downregulation of cyclin D1, thereby inhibiting cell cycle progression.
Modulating effect of hesperetin on the molecular expression pattern of apoptotic and cell proliferative markers in 7,12-dimethylbenz(a)anthracene-induced oral carcinogenesis
Published in Archives of Physiology and Biochemistry, 2020
Sukumar Babukumar, Veerasamy Vinothkumar, Duraisamy Ramachandhiran
The molecular approach of cancer chemoprevention study utilises apoptotic and cell proliferative proteins and focus on the investigation of the new anticancer agent from a natural source. The tumour suppressor protein p53 is the guardian of the genome and is involved in the regulation of apoptosis, gene amplification and DNA recombination. Mutated-p53 is strongly implicated in several carcinogenesis through the defect in cell-cycle progression and protects cells from apoptosis (Hientz et al.2017). Cyclin-D1 is an important cell-cycle protein that regulates the cell cycle from G1 to S phase through cyclin-dependent kinases. Dysfunction of cell cycle leads to overexpression of cyclin-D1 associated with many cancer types including oral cancer (Duronio and Xiong 2013). Mitochondria by releasing proapoptotic factors contribute to both the caspase-dependent and independent pathways of apoptosis (Alam et al. 2011). In addition initiator (casp-9) and effector (casp-3) caspases are responsible for the stimulation of apoptosis. Decreased caspases expression may prevent the cell from apoptosis that leads to tumorigenesis (Fogarty and Bergmann 2017).
Cyclin D1 regulates osteoarthritis chondrocyte apoptosis via WNT3/β-catenin signalling
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Yi-Yue Chen, You Chen, Wan-Chuan Wang, Qi- Tang, Ren Wu, Wei-Hong Zhu, Ding Li, Le-Le Liao
And, MMP-13 was increased as the grade of OA increased. Cyclin D1, as the central players of cell cycle regulation, plays a vital role in the transition from G1 phase to S phase. Chondrocyte apoptosis was the pathogenic factor of OA. Beier et al. [21] revealed that PTHrP and TGF-beta could activate transcription of the Cyclin D1 promoter to protect the cartilage. Zan et al. [13] found that silenced Cyclin D1 gene could suppress the proliferation and induces apoptosis of rat chondrocytes in IL-1β-induced OA. However, the definite mechanism was not well established. This study used overexpression and gene-silencing methods, aimed to comprehensively analysis the role of Cyclin D1 for OA. Results identified that overexpressing Cyclin D1 could prevent the occurrence of OA. Zheng et al. [21] revealed that there was a connection between Cyclin D1 and Wnt-β-catenin signalling pathway. Expression of β-catenin and Cyclin D1 in the Wnt/β-catenin signalling pathway is inhibited by DKK-1, a Wnt/β-catenin signalling pathway inhibitor.
Related Knowledge Centers
- Cullin
- Cyclin
- Cyclin E
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- Amino Acid
- Cell Cycle
- G1/S Transition
- Cyclin-Dependent Kinase
- Anaphase-Promoting Complex
- Cyclin-Dependent Kinase 2