P53调节蛋白ASPPs的分子生物学特性及其与肿瘤的关系

ASPPs（含有富含脯氨酸结构域、锚蛋白重复区及SH3结构域的蛋白）是一类新发现的凋亡调节蛋白,它们能够特异性地调节P53蛋白家族的凋亡活性。ASPPs由ASPP1、ASPP2和iASPP3个同源性很高的成员组成,其中ASPP1、ASPP2可正向调节P53活性,而iASPP的功能恰好与之相反;越来越多的研究表明,此类蛋白功能多样,可参与多条细胞信号通路。ASPPs的异常调控与肿瘤发生、发展密切相关,有望成为肿瘤治疗的新靶点。     

microRNAs与TP53基因调控网络研究进展

TP53基因(编码p53蛋白)作为一个重要的抑瘤基因,通过调控一系列信号转导通路广泛参与了多种恶性肿瘤的发生发展,一直是肿瘤分子生物学研究领域的热点.最近的研究发现,microRNAs(miRNAs)参与了TP53的信号通路,它们之间存在着复杂的调控网络.一方面,p53通过调控一些miRNAs的转录及转录后成熟,促进细胞周期阻滞、诱导细胞凋亡和衰老,抑制肿瘤发生.另一方面,许多miRNAs,如miR-25、miR-30d、miR-125b和miR-504等可直接调控p53的表达与活性,参与TP53信号通路的调节,还有一些miRNAs则通过调节p53上下游基因,发挥重要的生物学功能.其中,最具有代表性的是miR-34家族,它们受p53直接调控并参与TP53信号通路,通过靶向抑制多个TP53信号通路关键分子的表达,发挥抑瘤作用.此外,它们还可以通过抑制沉默信息调节子,增强p53的活性,反馈调节TP53信号通路.miRNAs与TP53之间调控网络的研究,是对TP53抑瘤机制的重要补充.     

EGCG在肿瘤预防及治疗中作用的分子机制

表没食子儿茶素没食子酸酯(EGCG)可多通路多途径预防和治疗肿瘤。本文综述了EGCG通过Nrf2通路预防肿瘤,从膜受体通路、线粒体通路、P53-Bax、67-LR-eEF1A、VEGF等通路促进肿瘤细胞的凋亡及周期阻滞,抑制肿瘤的侵袭和迁移的研究新进展。     

小分子G蛋白R-Ras介导的细胞信号转导通路及其生物学功能

R-Ras属于小分子G蛋白Ras超家族,在细胞信号转导通路中起着分子开关的作用,具有调控细胞黏附、促进细胞凋亡、抑制细胞运动、调节细胞形态等多种生物学功能。R-Ras和Ras家族的其他成员一样,结合GTP时处于激活状态,即信号通路开启状态,能够与下游因子相互作用;通过上游信号的调节及其下游效应物,将胞外信号转导到胞内,调节细胞的相关生物学功能。最近的研究提示R-Ras与乳腺癌等肿瘤的发生具有相关性,对其深入研究有可能为肿瘤发生机制的阐明提供分子基础。我们对R-Ras介导的细胞信号转导通路及其生物学功能进行简要综述。     

肿瘤坏死因子信号传导的分子机理

肿瘤坏死因子(tumor necrosis factor,TNF)是一种具有多种生物学效应的细胞因子,其生物学效应包括促进细胞生长、分化、凋亡及炎症诱发等.TNF的生物学效应都是通过细胞表面的两种TNF受体引发的.TNF的信号传导通路主要包括细胞凋亡及转录因子NF-kB和JNK蛋白激酶的激活.这3条信号传导通路之间及各通路内部含有各种调节机制,使TNF的各种生物学功能协调发挥出来.从1994年到现在,对肿瘤坏死因子信号传导通路的分子机理研究取得了一系列突破性进展,在细胞信号传导研究领域中树立了成功的典范.     

Gadd45a在抑制细胞转化和肿瘤恶性进展中的作用

Gadd45a,一个受p53和BRCA1调节的生长阻滞和DNA损伤基因,在抑制细胞转化和肿瘤恶性进展中扮演重要的角色.Gadd45a可以通过抑制细胞生长以及促进DNA损伤修复等间接或者直接方式维持基因组稳定性,从而抑制细胞转化和肿瘤的恶性进展.此外,Gadd45a还可通过对一些信号传导通路的调节,参与肿瘤发生发展的抑制.     

MDM2/MDMX异二聚体及MDMX磷酸化调控p53的研究进展

p53作为肿瘤抑制因子在维持机体内稳态和抑制肿瘤发生发展中起到关键作用。超过半数的人类肿瘤中都存在p53的突变。突变的p53具有"获得性功能",反而促进肿瘤的发生、转移和耐药。MDM2和MDMX是两个最主要的p53负调控蛋白,二者是同源蛋白,可以独自或以异二聚体的方式调控p53。在多种刺激信号下,MDM2/MDMX异二聚体对p53的负调控作用被抑制,使得p53活化进而激活下游复杂的信号网络,维持细胞内稳态。磷酸化修饰是MDMX调节的重要方式之一,对其自身的稳定性、核定位以及与MDM2、p53的相互作用均有影响。该文对以上内容进行简要综述,并对现有治疗靶标和小分子化合物进行讨论,为进一步开发新的有效的肿瘤治疗策略提供思路。     

哺乳动物Hippo信号通路:肿瘤治疗的新标靶

Hippo信号通路是首次在果蝇中发现具有调节细胞增殖与凋亡作用的信号通路。最近发现果蝇Hippo信号通路的组成、分子作用机制和生物学功能在进化过程中高度保守。Hippo信号通路在胚胎发育中对细胞的生长分化、组织器官形成以及成体干细胞的维持和自稳态的保持等方面具有重要作用。同时,Hippo信号通路与Wnt信号通路、Notch信号通路等相互作用、密切联系,在肿瘤的发生、发展过程中也起到关键作用。文章综述了哺乳动物Hippo信号通路的作用机理、与其他信号通路和蛋白质因子的相互联系及与肿瘤的关系,对于肿瘤的诊断、预防和治疗具有一定的参考价值。     

蛋白质体外磷酸化方法的建立

蛋白质的磷酸化与去磷酸化调节方式在细胞信号传递过程中占有极其重要的位置. 建立鉴定蛋白质磷酸化的可靠方法具有重要意义. 毛细血管扩张性共济失调症突变蛋白(ataxia-telangiectasia mutated, ATM）是直接感受DNA双链断裂损伤,并起始诸多DNA损伤信号反应通路的主开关分子. 电离辐射（IR）细胞学反应中,ATM激酶可通过磷酸化活化p53蛋白,原核表达p53融合蛋白,免疫沉淀IR活化的野生型ATM蛋白,进行蛋白质的体外磷酸化反应. 实验验证了ATM对p53蛋白的磷酸化作用. 这一方法的建立可为研究细胞信号转导途径中蛋白激酶对底物的磷酸化作用及筛查激酶底物提供标准化的技术手段.     

肿瘤中与survivin有关的信号通路及分子以及靶向survivin的治疗前景

Survivin在细胞内环境稳定和肿瘤的形成中起重要的作用,在肿瘤的治疗中,survivivin的靶向治疗调节与一些典型的信号通路和一系列生长因子有关。众所周知,survivin是一个小的凋亡蛋白抑制因子,也是一个主要的抗癌靶标,与细胞分裂和凋亡抑制有关,它在大部分正常组织中缺失但在大部分癌组织中过表达。Survivin是一个与众多细胞信号通路有关的节点蛋白,这些通路协调各种细胞因子、转录网络和修饰基因,通过调节癌细胞内环境稳定直接或间接促进细胞增殖。临床前研究数据表明,survivin的抑制可以降低细胞增殖促进凋亡,增加细胞对细胞毒药物和放疗的敏感性,其过表达与不良预后和治疗耐受有关。因此对于癌症治疗,survivin是一个潜在的靶标。     

The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target

NAD⁺ metabolism plays key roles not only in energy production but also in diverse cellular physiology. Aberrant NAD⁺ metabolism is considered a hallmark of cancer. Recently, the tumor suppressor p53, a major player in cancer signaling pathways, has been implicated as an important regulator of cellular metabolism. This notion led us to examine whether p53 can regulate NAD⁺ biosynthesis in the cell. Our search resulted in the identification of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2), a NAD⁺ synthetase, as a novel downstream target gene of p53. We show that NMNAT-2 expression is induced upon DNA damage in a p53-dependent manner. Two putative p53 binding sites were identified within the human NMNAT-2 gene, and both were found to be functional in a p53-dependent manner. Furthermore, knockdown of NMNAT-2 significantly reduces cellular NAD⁺ levels and protects cells from p53-dependent cell death upon DNA damage, suggesting an important functional role of NMNAT-2 in p53-mediated signaling. Our demonstration that p53 modulates cellular NAD⁺ synthesis is congruent with p53’s emerging role as a key regulator of metabolism and related cell fate.     

Cell surface receptors in lysophospholipid signaling

The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), regulate various signaling pathways within cells by binding to multiple G protein-coupled receptors. Receptor-mediated LPA and S1P signaling induces diverse cellular responses including proliferation, adhesion, migration, morphogenesis, differentiation and survival. This review will focus on major components of lysophospholipid signaling: metabolism, identification and expression of LPA and S1P receptors, general signaling pathways and specific signaling mechanisms in mouse embryonic fibroblasts. Finally, in vivo effects of LP receptor gene deletion in mice will be discussed.     

Control of p53 and NF-κB signaling by WIP1 and MIF: role in cellular senescence and organismal aging

The stress-activated signaling pathways, p53 and NF-κB, have a major role in the regulation of cellular senescence and organismal aging. These ancient signaling networks display functional antagonism via negative autoregulatory circuits. WIP1 (wildtype p53-induced phosphatase 1) and MIF (macrophage migration inhibitory factor) are signaling molecules which link together the p53 and NF-κB pathways via positive and negative feedback loops. It seems that the efficiency of the p53 signaling pathway declines during aging whereas that of NF-κB is clearly enhanced. Moreover, p53 is an important trigger of cellular senescence while NF-κB signaling seems to be involved in the induction of the senescence-associated secretory phenotype (SASP). MIF is a pro-inflammatory cytokine which inhibits the function of p53 signaling whereas it is linked to NF-κB signaling via a positive feedback loop. MIF knockout mice are healthier and live longer than their wild-type counterparts. An increased level of MIF can support inflammatory responses via enhancing NF-κB signaling and repressing the function of p53. p53 is an inducer of the expression of WIP1 which can subsequently inhibit NF-κB signaling. Several observations indicate that the activity of WIP1 decreases during the aging process, this being probably attributable to the decline in p53 function. Decreased WIP1 activity potentiates the activity of p38MAPK and NF-κB signaling leading to premature cellular senescence as well as low-level chronic inflammation. We will review the findings linking WIP1 and MIF to specific signaling responses of p53 and NF-κB and discuss their role in the regulation of cellular senescence and organismal aging.     

miRNAs与衰老相关信号通路的研究进展

miRNAs是一类负调控基因表达的内源性非编码小分子RNA,在细胞衰老过程中发挥重要作用. 细胞衰老是指可增殖细胞在各种应激下出现细胞周期阻滞,并且丧失增殖能力,进入一种不可逆的、相对稳定的状态. p53、p21、p16、SIRT1、胰岛素/IGF-1及mTOR等蛋白是衰老相关信号通路中的重要分子,参与细胞衰老过程. 研究表明,miRNAs可以通过调控这些衰老相关蛋白所在的信号通路,促进或延缓细胞衰老. 本文综述细胞衰老相关的miRNAs,以及它们对衰老相关信号通路的影响,为深化认识衰老和衰老相关疾病的分子机制奠定基础.     

The 14-3-3 proteins in regulation of cellular metabolism

Thirty years ago, it was discovered that 14-3-3 proteins could activate enzymes involved in amino acid metabolism. In the following decades, 14-3-3s have been shown to be involved in many different signaling pathways that modulate cellular and whole body energy and nutrient homeostasis. Large scale screening for cellular binding partners of 14-3-3 has identified numerous proteins that participate in regulation of metabolic pathways, although only a minority of these targets have yet been subject to detailed studies. Because of the wide distribution of potential 14-3-3 targets and the resurging interest in metabolic pathway control in diseases like cancer, diabetes, obesity and cardiovascular disease, we review the role of 14-3-3 proteins in the regulation of core and specialized cellular metabolic functions. We cite illustrative examples of 14-3-3 action through their direct modulation of individual enzymes and through regulation of master switches in cellular pathways, such as insulin signaling, mTOR- and AMP dependent kinase signaling pathways, as well as regulation of autophagy. We further illustrate the quantitative impact of 14-3-3 association on signal response at the target protein level and we discuss implications of recent findings showing 14-3-3 protein membrane binding of target proteins.