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p53 function is of critical importance in suppressing human cancer formation, highlighted by the fact that the majority of human tumors harbor compromised p53 activity. In normal cells, p53 is held at low levels in a latent form and cellular stress results in the rapid stabilization of p53. Mdm2 mediates ubiquitin-dependent degradation of p53 which plays a key role in maintaining cellular p53 levels. Ubiquitination was, until recently, considered a straightforward system involved in p53 degradation, but recent work has demonstrated how ubiquitination can alter p53 activity, not stability. In this review we summarize current understanding on p53 ubiquitination by Mdm2 with a particular focus on how the balance between protein levels and other post-translational modifications will direct the p53 response. 相似文献
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The catenin p120 is involved in many processes, including cell-cell adhesion and cancer. Recent work explores whether p120 independently regulates two key binding partners, RhoGTPase and cadherin. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(7):898-902
The p53 tumor suppressor pathway is inactivated in most if not all human tumors. In about 50% of the cases this is accomplished directly by gene mutations. The tumors that retain wild type p53 frequently show defects either in effector target genes, or in the expression of p53 regulatory proteins. The Mdm2 protein is generally considered THE master regulator of the p53 tumor suppressor activity. Recently, however, the Mdm2-related protein Mdmx is taking the stage in the p53-Mdm2-Mdmx play. We summarize here observations unambiguously assigning a critical role for the Mdmx protein in the regulation of p53 function during development and tumor formation. 相似文献
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目的:探讨HCC组织中的核心蛋白、突变p53、Mdm2、Bcl-2的表达以及其相关性,探讨HCV核心蛋白是否有可能促进p53突变、Mdm2和Bel-2的表达.方法:收集手术切除HCC组织42例,采用免疫组织化学EnVision法检测HCC组织核心蛋白、突变p53、Mdm2、Bel-2的表达,用统计学方法及临床联系分析它们之间的关系.结果:C蛋白、p53、Mdm2和Bcl-2在HCC癌组织中的表达率分别为40.5%、47.6%、75.6%、83.3%;4组强度等级资料Kruskal.Wallis秩和检验H=19.01,差异性显著(p=0.000),Mann-Whimey U test:C蛋白和p53、Mdm2、Bcl-2蛋白问的P值分别0.43、0.009、0.00;C蛋白与突变p53、Bcl-2阳性强度两者间相关性检验P值分别为0.000、0.914,相关系数rs分别为0.67、0.08;突变p53与Mdm2、Bcl-2两者相关性检验P值为0.000、0.27,相关系数rp为0.72、0.32.结论:在HCV核心蛋白表达的HCC中核心蛋白可能促进野生型p53突变和表达;突变p53很可能促进Mdm2的表达;核心蛋白和突变p53都有可能促进Bcl-2蛋白的表达;HCV相关的HCC中这些蛋白的变化很可能促进肝细胞增殖或恶性生长. 相似文献
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Christian E. Cuba Alexander R. Valle Giancarlo Ayala-Charca Elizabeth R. Villota Alberto M. Coronado 《Systems and synthetic biology》2015,9(3):77-84
Biomolecular networks that present oscillatory behavior are ubiquitous in nature. While some design principles for robust oscillations have been identified, it is not well understood how these oscillations are affected when the kinetic parameters are constantly changing or are not precisely known, as often occurs in cellular environments. Many models of diverse complexity level, for systems such as circadian rhythms, cell cycle or the p53 network, have been proposed. Here we assess the influence of hundreds of different parameter sets on the sensitivities of two configurations of a well-known oscillatory system, the p53 core network. We show that, for both models and all parameter sets, the parameter related to the p53 positive feedback, i.e. self-promotion, is the only one that presents sizeable sensitivities on extrema, periods and delay. Moreover, varying the parameter set values to change the dynamical characteristics of the response is more restricted in the simple model, whereas the complex model shows greater tunability. These results highlight the importance of the presence of specific network patterns, in addition to the role of parameter values, when we want to characterize oscillatory biochemical systems.
Electronic supplementary material
The online version of this article (doi:10.1007/s11693-015-9173-y) contains supplementary material, which is available to authorized users. 相似文献9.
p53 Mutations: Gains or losses? 总被引:21,自引:0,他引:21
Although the case for p53 as a tumor suppressor gene appears very strong, one should still keep an open eye for the possibility that mutations in p53 do not necessarily imply a mere loss of "suppressor" activity. It is still possible that the presence of a p53 mutation in a tumor contributes, in a dominant positive manner, to tumorigenesis. In other words, certain p53 mutants may well be oncogenic in their own right, and carry distinct activities that promote growth deregulation and malignant progression. Elucidating this issue also has practical implications, since the nature of the resident mutations may greatly dictate the consequences of attempts to reintroduce wild-type (wt) p53 into particular types of tumor cells. There are two major obstacles along the road to meaningful answers: the limitations of the experimental systems used for evaluating the biological activities of wt and mutant p53 and a fundamental lack of knowledge about the relevant biochemistry of the p53 protein. These two aspects constitute primary experimental challenges for investigators in the field. 相似文献
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p53: The Janus of autophagy? 总被引:2,自引:0,他引:2
The autophagy pathway functions in adaptation to nutrient stress and tumour suppression. The p53 tumour suppressor, previously thought to positively regulate autophagy, may also inhibit it. This dual interplay between p53 and autophagy regulation is enigmatic, but may underlie key aspects of metabolism and cancer biology. 相似文献
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The ubiquitin-proteasome pathway has become an increasingly important regulatory mechanism for protein function. Countless proteins are degraded by the addition of polymeric ubiquitin chains, but more recently, monoubiquitination has emerged as a mechanism for regulatory functions other than proteasomal degradation. Monoubiquitination acts as a signal in nuclear export for the tumor suppressor protein p53. Different levels of Mdm2 are capable of inducing both mono- and polyubiquitination in a dosage dependent manner, thus determining p53's fate. Our findings demonstrate monoubiquitin-mediated protein trafficking can be expanded to nuclear-cytoplasmic shuttling, and also imply similar scenarios may apply to other cellular factors. 相似文献
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Mdm2(murine double minute 2,又称为Hdm2)和Mdm X(murine double minute X,又称为Hdm4)的异常过表达与近半数的癌症直接相关,设计靶向Mdm2/Mdm X-p53蛋白质相互作用位点抑制剂,解除Mdm2和Mdm X对p53的抑制作用有着重要的临床意义。尽管Mdm2和MdmX结构非常相似,但仅有Mdm2小分子抑制剂的筛选和设计研究较深入。对依据nutlin分子构效关系、结构生物学、组合化学多重优化等手段筛设计MdmX抑制剂的研究进展进行简述,并讨论天然产物库在筛选Mdm X/Mdm2抑制剂新型结构框架的应用前景。 相似文献
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p53 is a key tumor suppressor protein that has numerous functions. Its primary mode of action has generally been ascribed to the induction of cell-cycle arrest, apoptosis, or senescence upon stress. Li et al. challenge this dogma with evidence that all three of these programs are dispensable for p53's tumor suppressive role. 相似文献
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HIF-1alpha and p53: the ODD couple? 总被引:5,自引:0,他引:5
Tumor hypoxia activates hypoxia-inducible factor-1 (HIF-1) and induces the accumulation of the tumor suppressor p53. HIF-1 signaling stimulates angiogenesis and mediates cellular adaptation to hypoxia, whereas p53 promotes hypoxia-induced apoptosis. A recent article provides in vitro biophysical evidence supporting a direct interaction between p53 and the oxygen-dependent degradation domain of the HIF-1alpha subunit. The article identifies potential structural parameters required for this interaction and suggests an alternative mechanism by which p53 might impact tumor response to therapy. 相似文献
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p53 in the cytoplasm: a question of overkill? 总被引:5,自引:0,他引:5