核糖体蛋白参与调控p53诱导活化的分子机制

核转录因子p53是重要的肿瘤抑制因子,具有DNA损伤修复、促细胞凋亡、促细胞分化及增殖抑制等功能,并通过调控细胞周期行进和促进细胞凋亡发挥肿瘤抑制功能。原癌蛋白MDM2为p53的E3泛素化连接酶,MDM2－p53信号轴的功能异常与多种恶性肿瘤的发生发展相关。核糖体蛋白（RP）是蛋白质合成反应的关键调节蛋白,其功能失常与多种疾病相关。近年来的研究发现,RP能通过调节MDM2－p53信号轴在p53相关性肿瘤调控中发挥重要作用。我们根据目前的研究进展,对RP－MDM2－D53信号轴进行简要综述。     

p63和p63参与p53依赖的细胞凋亡过程

人们通常用经典的操作式学习方法来训练动物的行为 ,使动物学会根据外部信号 (如声音 )产生特定的行为反应 ,以获取奖赏 (如食物 )。而本文的作者用脑内植入微电极进行脑区刺激的方法教会动物如何学习 ,可以去除用来产生信号和奖赏的外部环境对实验的限制。这一动物模型使操作者能远距离地指挥动物的行为 ,很像控制智能机器人的方法。电刺激能否产生等同于信号或奖赏的效应 ,取决于它所刺激的脑区。作者在自由活动大鼠的躯体感觉皮层 (ＳＩ)左右两侧胡须代表区和内侧前脑束 (ＭＦＢ)内植入电极加以刺激 ,以产生信号和奖赏效应 ,据此准确地指…     

抑癌基因p53与细胞自噬

细胞自噬(autophagy)是一种在进化上高度保守的代谢通路,它发生的分子机制和信号调控途径相当复杂,其中mTOR信号通路和Beclin1复合物发挥了最重要的调控作用,p53也是细胞自噬重要的调节因子。研究发现,p53可通过多种途径调节细胞自噬水平,这主要决定于它的亚细胞定位。在细胞核中,p53可通过多种方式上调细胞自噬;而在细胞质中,p53对细胞自噬具有负性调节作用,可抑制细胞自噬的发生。探究清楚p53与细胞自噬之间的调控关系将有助于人类正确认识由于细胞自噬功能异常所诱导的肿瘤的发生发展过程,从而最终攻克各种肿瘤性疾病。     

p53家族及其通路相关蛋白调节母性生殖的新功能

p53是一种重要的抗癌基因,同时它也是机体感受环境压力并进行相应调节的关键基因之一。最近的研究发现东亚人群p53 Arg72Pro受到冬季温度自然选择,表明p53可能在生殖中发挥作用。同时,p53及其通路中的癌基因鼠双微体2(Murinedoubleminute2,Mdm2)、MdmX和Hausp(Herpesvirus-associated ubiquitin-specific protease)基因的单核苷酸多态性(Single nucleotide polymorphisms,SNP)与女性生殖疾病易感性相关。P53蛋白通过其DNA结合区(DNA-binding domain,DBD)调控白血病抑制因子(Leukaemiainhibitory factor,LIF)表达,从而影响胚胎植入过程,实现其在母性生殖中的作用。p53通路中Mdm2、MdmX和Hausp可以调控P53蛋白的表达水平和活性,同时还可以在胚胎植入时准确的调控p53的表达水平,促进胚胎植入;P53家族成员P63、P73具有P53相似的DBD区,但P63和P73是通过别的途径影响到母性生殖;在卵母细胞受到射线或者化学损伤后,P63能促进其凋亡,减少畸型的产生;P73能影响纺锤体复合物的组装,而纺锤体复合物缺失将导致胚泡质量低下,微管结合的动粒缺失和细胞非整倍性的增加。文章主要综述了p53家族、p53通路中的相关蛋白对母性生殖的影响,为提高IVF-ET成功指出了新方法,同时也为不明原因的不孕患者提供了新的诊断思路,将有助于制定合理的个性化治疗不孕方案。     

调控p53蛋白的转录因子

肿瘤抑制因子p53被称为"分子警察",它在维持细胞正常生长及抑制恶性增殖过程中起重要作用。p53的表达水平受多种因素影响,其中转录水平的调控是基因发挥功能的一个重要步骤。因此,针对调控p53蛋白的转录因子这一环节阐明p53发挥功能的分子机理,有望为肿瘤治疗、预防和新药研发提供新的靶标。本文着重对调控p53蛋白的转录因子进行综述。     

miR-155 通过p53/p21 调控前列腺癌细胞周期

目的:探讨miR-155对前列腺癌细胞周期的影响及其分子机制。方法:通过转染anti-miR-155抑制前列腺癌DU145和PC-3细胞中miR-155水平后,采用流式细胞术观察细胞周期的变化,western blot和RT-PCR观察p53和p21蛋白及CDK2和cyclin蛋白和m RNA表达的变化。结果:与对照组相比,DU145和PC-3细胞转染anti-miR-155后,G2/M期细胞阻滞,S期细胞数比例显著增加(P0.05),p53和p21蛋白和m RNA表达水平显著增加(P0.01),CDK2和cyclin E蛋白和m RNA表达均显著降低(P0.01)。结论:miR-155可影响人前列腺癌细胞的周期,可能与其调节p53、p21及其下游的CDK2和cyclin E的表达相关。     

抑癌因子ARF的非p53调节通路

ARF蛋白是INK4a基因位点编码产物之一,是一种重要的肿瘤抑制因子。ARF可结合原癌蛋白Mdm2,稳定p53,将细胞周期阻断在G1期和G2/M转换期,或诱导细胞凋亡。有关ARF的p53依赖性作用已有较多报道。该文主要以ARF对E2F1、DP1、E2F1/DP1、NPM/B23和c-Myc等的调控为例,对ARF的非p53调节通路做一综述。     

p53直接调控microRNA及其靶基因的高通量筛选

通过对676条人microRNA进行筛选,共得到了53条新的具有p53-DNA结合位点且调控p53上游转录因子和下游靶基因的microRNA．结合已有蛋白质互作关系与microRNA调控信息,构建了p53-microRNA相互作用网络图,其中FAS受多条microRNA调控,FAS是介导细胞凋亡的关键因子,因此,FAS-microRNA的相互作用可能在细胞凋亡途径中起着关键的作用．随后,提出了microRNA参与p53调控的假设机制,认为p53调控靶基因与microRNA的同时也受上游转录因子与microRNA的调控,从而形成了以p53为中心的一种平衡,当这种调控平衡一旦被打破则会引起信号通路的紊乱,从而可能引发相应的疾病．对这53条microRNA进行靶基因预测,共得到15 500个靶基因,对这些基因的出现频率进行聚类分析共得到27个簇,将出现频率大于10的基因进行功能注释分析,发现多数基因功能属于近来发现的p53靶基因新的功能分类——细胞粘连和细胞运动,目前研究认为,p53通过与这些具有细胞粘连和运动功能的靶基因结合来抑制肿瘤的迁移．通过对15 500个基因进行功能注释分析,得到了30条感兴趣的参与细胞周期调控、细胞凋亡和细胞增殖的microRNA,其中有9条microRNA于3种生物学进程均有参与,这9条microRNA分别是: hsa-mir-181a-1、hsa-mir-181b-1、hsa-mir-181c、hsa-mir-181d、hsa-mir-195、hsa-mir-497、hsa-mir-495、hsa-mir-543和hsa-mir-548c．这暗示着这9条microRNA在p53信号通路的调节中可能起着关键的作用,它们互相作用共同调节着多个p53信号环路．最后在36个物种的基因组中对这30条microRNA进行了同源性搜索与保守性分析,结果发现有10条高度保守的且为目前数据库所未收录的microRNA．这10条microRNA分别是：hsa-mir-497、hsa-mir-495、hsa-mir-543、hsa-mir-19a、hsa-mir-19b-1、hsa-mir-200b、hsa-mir-448、 hsa-mir-28、hsa-mir-455和hsa-mir-590．     

抑癌蛋白p53乙酰化修饰的调控网络

p53是细胞内最重要的抑癌蛋白质之一;细胞对p53分子功能的调控主要通过一系列翻译后修饰(PTMs)完成。其中,乙酰化修饰既可在总体水平调控p53的转录活性,又可位点特异性地调控p53依赖的转录选择性,进而精确控制p53在细胞周期阻滞、凋亡、衰老、自噬和代谢等关键生物学过程中的作用。本综述以p53乙酰化修饰研究的时间脉络为轴,首先总结了发生在p53各结构域内乙酰化修饰的建立机制,包括催化p53位点特异性乙酰化发生的乙酰基转移酶,以及各位点乙酰化修饰对p53分子功能调节的机制。其次,本综述总结了参与去除p53乙酰化修饰的关键去乙酰基酶家族,以及这些因子参与调控p53分子功能的生物学意义。同时,本文综述了能够特异性读取p53乙酰化修饰状态的识别蛋白质,以及这些识别蛋白质与p53互作,进而协同调控下游靶基因转录的分子调控网络。此外,本文概述了p53乙酰化修饰与其它类型翻译后修饰之间的“交谈”,以及这些修饰之间通过时空特异互作方式影响p53功能的分子机制。最后,本文基于p53乙酰化修饰,对肿瘤分子医学的研究前景进行讨论与展望。     

p53蛋白泛素化修饰的研究进展

p53具有抑制肿瘤细胞增殖的作用,但是细胞内p53蛋白的堆积反而加速细胞衰老或凋亡,因此对p53进行严格的调控显得格外重要.泛素化、磷酸化和乙酰化是p53蛋白最主要的几种修饰形式,但近来研究表明泛素化对p53调控发挥着中心作用.MDM2是主要的负调节因子,其具有泛素连接酶的活性,早先的研究认为MDM2的作用主要是特异性结合p53并介导其在蛋白酶作用下降解,但近来的研究发现MDM2还可以介导p53的核-浆交换,这种现象在DNA损伤时尤为明显.推测MDM2介导p53的泛素化在体内可能发挥着多种调控功能.     

抑癌基因p53与肿瘤研究的最新进展

p53基因是迄今为止已发现的与人类肿瘤发生相关性最高的抑癌基因,其主要生物学功能是通过调控DNA修复、细胞周期停滞和诱导细胞凋亡,维持基因组和细胞稳定,抑制肿瘤生长;肿瘤血管再生、微小RNA（microRNA,miRNA）及肿瘤干细胞是近几年来肿瘤发生机理研究领域的热点,本文综述了p53基因在肿瘤血管再生、miRNA、肿瘤干细胞中作用的最新研究进展及其在肿瘤治疗中的应用。     

New insights into p53 functions through its target microRNAs

The tumor suppressor p53 pathway, whose alterations are highly associated with all types of human cancers, plays an essential role in preventingtumor development and progression mostly through its downstream target genes. Over the last decade, a growing list of p53 microRNA （miRNA） targets has been identified as additional downstream players of this pathway. Further studies ofthese miRNAs have revealed their more complicated regulations and functions in executing and/or regulating p53 activity. Here, we review the p53 miRNA targets identified thus far, and discuss how they fine-tune p53 stress responses, mediate the crosstalk between p53 and other signaling pathways, and expand the role of p53 in other human diseases in addition to cancers.     

The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway

Aging is a multifactorial process characterized by the progressive deterioration of physiological functions. Among the multiple molecular mechanisms, microRNAs (miRNAs) have increasingly been implicated in the regulation of Aging process. However, the contribution of miRNAs to physiological Aging and the underlying mechanisms remain elusive. We herein performed high‐throughput analysis using miRNA and mRNA microarray in the physiological Aging mouse, attempted to deepen into the understanding of the effects of miRNAs on Aging process at the “network” level. The data showed that various p53 responsive miRNAs, including miR‐124, miR‐34a and miR‐29a/b/c, were up‐regulated in Aging mouse compared with that in Young mouse. Further investigation unraveled that similar as miR‐34a and miR‐29, miR‐124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co‐expression network analysis unveiled that the most down‐regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down‐regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR‐124 and miR‐29), which functioned as the antagonist of p21 in cell cycle regulation. Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence‐induction effect of miR‐124 and miR‐29. Moreover, these p53 responsive miRNAs were significantly up‐regulated during the senescence process of p21‐deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.     

Gene and microRNA expression in p53‐deficient day 8.5 mouse embryos

BACKGROUND: Neural tube defects (NTDs) are one of the most common human birth defects, with a prevalence of approximately 1 in 1000 live births in the United States. In animal studies, deletion of p53 leads to a significant increase in embryos that exhibit exencephaly. Whereas several studies have closely investigated the morphologic changes of p53‐deficient embryos, no study has reported the molecular‐level alteration in p53‐deficient embryos. Here we attempt to identify genes and microRNAs (miRNAs) modified by deletion of p53 in day 8.5 mouse embryos. METHODS: Mouse embryos from p53 heterozygous crosses were collected, genotyped, and embryos of similar genotype (+/+; +/?; ?/?) were pooled. RNA from the pooled samples was isolated to determine mRNA and miRNA expression levels using Whole Genome Bioarrays and Low Density Arrays, respectively. RESULTS: In p53 ?/? embryos, 388 genes showed statistically significant alteration in gene expression of more than twofold compared to p53 +/+ embryos. Expression of p53 and well known p53 target genes, such as p21 and cyclin G1, were significantly down‐regulated in p53 ?/? embryos. In contrast, expression of other p53 target genes, such as Mdm2, Noxa, and Puma, were unchanged. We also identified six genes (Csk, Itga3, Jarid2, Prkaca, Rarg, and Sall4), known to cause NTDs when deleted, that are also down‐regulated in p53 ?/? embryos. Finally, five miRNAs (mir‐1, mir‐30e‐3p, mir‐142‐3p, mir‐301, and mir‐331) also showed statistically significant alterations in expression levels in p53 ?/? embryos compared to p53 +/+ embryos. Combined analysis of the experimental data using stepwise regression model and two publicly available algorithms identified putative target genes of these miRNAs. CONCLUSIONS: Our data have identified genes and miRNAs that may be involved in the mechanisms underlining NTDs and begin to define the developmental role of p53 in the etiology of NTDs. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

突变体p53研究进展

抑癌基因突变是癌症发生过程中一个极为关键的事件。p53作为体内最重要的抑癌基因之一, 在人类癌症中发生突变的频率高达50%。同时, p53突变也是人类遗传病Li-Fraumeni综合征的主要病因。p53最常见的突变形式是错义突变, 所形成的突变体p53不但失去了野生型p53的抑癌功能, 而且还获得了一系列类似于癌基因的功能, 促进了肿瘤的进程。文章拟对突变体p53的结构功能改变, 获得癌基因活性的分子机制, 以及近年来对封闭突变体p53活性所进行的探索等研究方向所取得的进展做一综述。