抑癌蛋白p33(ING1)对肿瘤作用的研究进展

p33(ING1)是生长抑制基因(ING1)编码的重要抑癌蛋白,具有抑制细胞生长﹑促进细胞老化﹑维持基因组稳定性、作用于细胞周期调控点等作用,其失活与肿瘤的发生、发展密切相关。本文就近年来有关p33(ING1)的结构、功能及其在肿瘤中的失活机制、临床应用前景等方面的研究进展进行了概述。     

Src Regulates the Activity of the ING1 Tumor Suppressor

The INhibitor of Growth 1 (ING1) is stoichiometric member of histone deacetylase (HDAC) complexes and functions as an epigenetic regulator and a type II tumor suppressor. It impacts cell growth, aging, apoptosis, and DNA repair, by affecting chromatin conformation and gene expression. Down regulation and mislocalization of ING1 have been reported in diverse tumor types and Ser/Thr phosphorylation has been implicated in both of these processes. Here we demonstrate that both in vitro and in vivo, the tyrosine kinase Src is able to physically associate with, and phosphorylate ING1, which results in a nuclear to cytoplasmic relocalization of ING1 in cells and a decrease of ING1 stability. Functionally, Src antagonizes the ability of ING1 to induce apoptosis, most likely through relocalization of ING1 and down regulation of ING1 levels. These effects were due to both kinase-dependent and kinase-independent properties of Src, and were most apparent at elevated levels of Src expression. These findings suggest that Src may play a major role in regulating ING1 levels during tumorigenesis in those cancers in which high levels of Src expression or activity are present. These data represent the first report of tyrosine kinase-mediated regulation of ING1 levels and suggest that kinase activation can impact chromatin structure through the ING1 epigenetic regulator.     

Microbial Regulation of p53 Tumor Suppressor

p53 tumor suppressor has been identified as a protein interacting with the large T antigen produced by simian vacuolating virus 40 (SV40). Subsequent research on p53 inhibition by SV40 and other tumor viruses has not only helped to gain a better understanding of viral biology, but also shaped our knowledge of human tumorigenesis. Recent studies have found, however, that inhibition of p53 is not strictly in the realm of viruses. Some bacterial pathogens also actively inhibit p53 protein and induce its degradation, resulting in alteration of cellular stress responses. This phenomenon was initially characterized in gastric epithelial cells infected with Helicobacter pylori, a bacterial pathogen that commonly infects the human stomach and is strongly linked to gastric cancer. Besides H. pylori, a number of other bacterial species were recently discovered to inhibit p53. These findings provide novel insights into host–bacteria interactions and tumorigenesis associated with bacterial infections.     

Tumor Suppressor Candidate 1 Suppresses Cell Growth and Predicts Better Survival in Glioblastoma

Glioblastoma (GBM) is the most common malignant brain tumor with poor prognosis and limited treatment options. Tumor suppressor candidate 1 (TUSC1) was recently identified as a potential tumor suppressor in human cancers. However, the expression and potential function of TUSC1 in GBM remain unclear. Herein, we report that TUSC1 is significantly decreased in GBM tissues and cell lines. Patients with high levels of TUSC1 displayed a significant better survival compared with those with low levels of TUSC1. Functional experiments demonstrated that exogenous expression of TUSC1 inhibited GBM cell proliferation and induced G1 phase arrest by down-regulating CDK4. Moreover, overexpression of TUSC1 retarded tumor growth in vivo. Together, our findings revealed that TUSC1 might be a crucial tumor suppressor gene and a novel therapeutic target for GBM.     

The Positive Regulation of p53 by the Tumor Suppressor VHL

The ubiquitin-mediated degradation of hypoxia-inducible factor-α (HIF-α) by a von Hippel-Lindau tumor suppressor protein (pVHL) is mechanistically responsible for controlling gene expression due to oxygen availability. Germline mutations in the VHL gene cause dysregulation of HIF and induce an autosomal dominant cancer syndrome referred to as VHL disease. However, it is unclear whether HIF accumulation caused by VHL mutations is sufficient for tumorigenesis. Recently, we found that pVHL directly associates and positively regulates the tumor suppressor p53 by inhibiting Mdm2-mediated ubiquitination, and by subsequently recruiting p53-modifying enzymes. Moreover, VHL-deleted RCC cells showed attenuated apoptosis or abnormal cell-cycle arrest upon DNA damage, but became normal when pVHL was restored. Thus, pVHL appears to play a pivotal role in tumor suppression by participating actively as a component of p53 transactivation complex during DNA damage response.     

生长抑制因子(ING)抑癌基因家族的研究进展

生长抑制因子(inhibitor of growth,ING)家族成员是候选的抑癌基因.ING蛋白参与磷脂酰肌醇介导的脂类信号转导通路及激素介导的通路,能够与组蛋白乙酰转移酶、去乙酰化酶等结合参与染色质的重构,调节基因的转录,与p53协同作用,抑制细胞生长,诱导细胞凋亡和DNA损伤修复.ING家族成员通过对基因表达的表观遗传学调控将细胞周期、细胞凋亡和衰老等生物学过程有机联系起来.     

抑癌蛋白PTEN及PDZ蛋白对其的调节

pten基因是迄今为止发现的第1个具有双特异性磷酸酶活性的抑癌基因,该基因的编码产物PTEN蛋白,是具有蛋白与脂质磷酸酯酶活性的双特异性磷酸酯酶,作为1种重要的信号分子参与细胞增殖、分化、黏附、迁移、凋亡以及基因转录的调控. 最近,关于PTEN在信号转导中的作用以及细胞内PTEN的调节机制研究较多,尤其是PDZ蛋白对PTEN的调节作用. PTEN蛋白包括1个氨基端（N端）磷酸酯酶区域,1个与脂质结合的C2区域和1个含有PDZ结合序列的羧基端（C端）区域. PDZ结构域通过识别目标蛋白羧基端PDZ结合序列与目标蛋白相互作用,调控多种重要的细胞生理过程和信号传导途径.本文就抑癌基因pten编码产物PTEN蛋白的结构、PTEN的生物学功能和PDZ蛋白对PTEN调节的研究进展进行综述.     

p33(ING1) enhances UVB-induced apoptosis in melanoma cells

The biological functions of the tumor suppressor ING1 have been studied extensively in the past few years since it was cloned. It shares many biological functions with p53 and has been reported to mediate growth arrest, senescence, apoptosis, anchorage-dependent growth, chemosensitivity, and DNA repair. Some of these functions, such as cell cycle arrest and apoptosis, have been shown to be dependent on the activity of both ING1 and p53 proteins. Two recent reports by Scott and colleagues demonstrate that p33(ING1) (one of the ING1 isoforms) translocates to the nucleus and binds to PCNA upon UV irradiation. Here we report that p33(ING1) mediates UV-induced cell death in melanoma cells. We found that overexpression of p33(ING1) increased while the introduction of an antisense p33(ING1) plasmid reduced the apoptosis rate in melanoma cells after UVB irradiation. We also demonstrated that enhancement of UV-induced apoptosis by p33(ING1) required the presence of p53. Moreover, we found that p33(ING1) enhanced the expression of endogenous Bax and altered the mitochondrial membrane potential. Taken together, these observations strongly suggest that p33(ING1) cooperates with p53 in UVB-induced apoptosis via the mitochondrial cell death pathway in melanoma cells.     

肿瘤抑制因子p53功能及其抗病毒作用研究进展

肿瘤抑制因子p53 作为基因组的守护者,能通过细胞周期调控和促进细胞凋亡而阻止癌细胞及机体肿瘤的发生,p53还能参与DNA损伤修复、调节机体代谢及调节繁殖生育等功能。除此以外,近年来研究发现,p53能通过促进病毒感染的细胞凋亡而起到抗病毒作用以及p53受IFN的调控和p53作为转录调控因子还能直接转录激活IRF9、IRF5、ISG15和TLR3等抗病毒基因,从而确定了p53在抗病毒反应中起到重要作用。这表明p53可能参与先天性免疫、获得性免疫及炎症反应而起到抗病毒的作用。     

Evidence for a Tumor Suppressor Role for the Large Tumor Suppressor Genes LATS1 and LATS2 in Human Cancer

The role of Large tumor suppressor LATS/Warts in human cancer is not clearly understood. Here we show that hLATS1/2 cancer mutations affect their expression and kinase activity. hLATS1/2 mutants exhibit a decreased activity in inhibiting YAP and tissue growth. Therefore, hLATS1/2 alleles from human cancer can be loss-of-function mutations.     

过表达人p33ING1b促进UV诱导的衰老细胞凋亡

p33 ^ING1b是肿瘤抑制基因ING1的主要表达形式,已有的研究表明,p33^ING1b参与了细胞的生长抑制、凋亡、染色质重塑、DNA损伤修复、肿瘤抑制等.但是,它在细胞衰老过程中的作用目前还不清楚.本研究分析了p33 ^ING1b基因在细胞衰老过程中的表达情况.结果发现,无论在mRNA水平还是在蛋白水平,p33 ^ING1b在衰老细胞中的表达均降低.通过构建和包装含p33^ING1b基因的重组腺病毒,将p33 ^ING1b导入衰老细胞中使其过表达,结果显示,p33^ING1b的过表达明显促进UV诱导的衰老细胞凋亡,提示p33I^NG1b在衰老细胞中的表达下调与衰老细胞抗凋亡有关.