Browsing by Subject "Cyclin-Dependent Kinase Inhibitor p21"
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Item Open Access A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle.(2012) Yong, Sheila T.Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis, a form of programmed cell death, has been extensively studied. However, since the developmental defects observed in Bat3‐null mouse embryos cannot be explained solely by defects in apoptosis, I investigated whether BAT3 is also involved in regulating cell‐cycle progression. Using a stable‐inducible Bat3‐knockdown cellular system, I demonstrated that reduced BAT3 protein level causes a delay in both the G1/S transition and G2/M progression. Concurrent with these changes in cell‐cycle progression, I observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21. p21 is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Additionally, I observed that the p21 turnover rate was also reduced in Bat3‐knockdown cells released from G2/M synchronization. My findings indicate that in Bat3‐knockdown cells, p21 continues to be synthesized during cell‐cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent cell‐cycle delay. Finally, I showed that BAT3 co‐localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. My study reveals a novel, non‐apoptoticrole for BAT3 in cell‐cycle regulation. By maintaining low p21 protein level during G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 into S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation, an event that promotes G2/M progression. BAT3 modulates these pro‐ and anti‐proliferative roles of p21 at least in part by regulating the translocation of p21 between the cytoplasm and nucleus of the cells to ensure proper functioning and regulation of p21 in the appropriate intracellular compartments during different cell‐cycle phases.Item Open Access Association between p21 Ser31Arg polymorphism and cancer risk: a meta-analysis.(Chinese journal of cancer, 2011-04) Ma, Hongxia; Zhou, Ziyuan; Wei, Sheng; Wei, QingyiP21 (CDKN1A), a key cell cycle regulatory protein that governs cell cycle progression from G1 to S phase, can regulate cell proliferation, growth arrest, and apoptosis. The Ser31Arg polymorphism is located in the highly conserved region of p21 and may encode functionally distinct proteins. Although many epidemiological studies have been conducted to evaluate the association between the p21 Ser31Arg polymorphism and cancer risk, the findings remain conflicting. This meta-analysis with 33 077 cases and 45 013 controls from 44 published case-control studies showed that the variant homozygous 31Arg/Arg genotype was associated with an increased risk of numerous types of cancers in a random-effect model (homozygote comparison: OR = 1.17, 95% CI = 0.99 to 1.37, P = 0.0002 for the heterogeneity test; recessive model comparison: OR = 1.16, 95% CI = 1.01 to 1.33, P = 0.0001 for the heterogeneity test). Stratified analysis revealed that increased cancer risk associated with the 31Arg/Arg genotype remained significant in subgroups of colorectal cancer, estrogen-related cancer, Caucasians, population-based studies, studies with matching information or a larger sample size. Heterogeneity analysis showed that tumor type contributed to substantial between-study heterogeneity (recessive model comparison: Χ(2) = 21.83, df = 7, P = 0.003). The results from this large-sample sized meta-analysis suggest that the p21 31Arg/Arg genotype may serve as a potential marker for increased cancer risk.Item Open Access Genetic variants of p27 and p21 as predictors for risk of second primary malignancy in patients with index squamous cell carcinoma of head and neck.(Molecular cancer, 2012-03-26) Wang, Zhongqiu; Sturgis, Erich M; Zhang, Fenghua; Lei, Dapeng; Liu, Zhensheng; Xu, Li; Song, Xicheng; Wei, Qingyi; Li, GuojunCell cycle deregulation is common in human cancer, and alterations of p27 and p21, two critical cell cycle regulators, have been implicated in the development of many human malignancies. Therefore, we hypothesize that p27 T109G polymorphism individually or in combination with p21 (C98A and C70T) polymorphisms modifies risk of second primary malignancy (SPM) in patients with index squamous cell carcinoma of head and neck (SCCHN).A cohort of 1,292 patients with index SCCHN was recruited between May 1995 and January 2007 at the M.D. Anderson Cancer Center and followed for SPM occurrence. Patients were genotyped for the three polymorphisms. A log-rank test and Cox proportional hazards models were used to compare SPM-free survival and SPM risk.We found that patients with p27 109 TG/GG, p21 98 CA/AA and p21 70 CT/TT variant genotypes had a worse SPM-free survival and an increased SPM risk than those with the corresponding p27109 TT, p21 98 CC, and p21 70 CC common genotypes, respectively. After combining the three polymorphisms, there was a trend for significantly increased SPM risk with increasing number of the variant genotypes (Ptrend = 0.0002). Moreover, patients with the variant genotypes had an approximately 2.4-fold significantly increased risk for SPM compared with those with no variant genotypes (HR, 2.4, 95% CI, 1.6-3.6).These results suggest that p27 T109G polymorphism individually or in combination with p21 (C98A and C70T) polymorphisms increases risk of SPM in patients with index SCCHN.Item Open Access Ubiquitylation of p53 by the APC/C inhibitor Trim39.(Proc Natl Acad Sci U S A, 2012-12-18) Zhang, Liguo; Huang, Nai-Jia; Chen, Chen; Tang, Wanli; Kornbluth, SallyTripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.