P53 induction accompanying G2/M arrest upon knockdown of tumor suppressor HIC1 in U87MG glioma cells

Hypermethylated in cancer 1 (HIC1) is a novel tumor suppressor gene (tsg) frequently silenced by epigenetic modification, predominantly by methylation in different tumors. HIC1 functionally co-operates with p53 in cultured cells as well as in transgenic animals to suppress tumors and has binding site on its promoter. Its over expression often leads to cell cycle arrests. Although HIC1 proven to have role as tsg, its regulation to cell cycle and dependency upon p53 is grossly unknown. In this study, we investigated the role of HIC1 in cell cycle and proliferation of glioma cell line U87MG which has wild type p53, in both serum-containing and serum-deprived medium. Microscopic analysis and MTT assay showed reduced cell number and rate of proliferation upon HIC1 knock down compared to control siRNA (p = 0.025) and untreated cells (p = 0.03) in serum-containing medium and serum-free medium (p = 0.014 vs control siRNA; p = 0.018 vs untreated cells). Cell cycle analysis revealed an arrest at G2/M phase of cell cycle with no demonstrable increase in apoptosis with both medium. An increased expression of p53 concomitant with HIC1 knockdown was observed. Furthermore P21, a p53 responsive gene, along with p27 was significantly increased in comparison with controls. Our results demonstrated an important role of HIC1 for the normal progression of cell cycle, and at molecular level, it could affect the homeostasis of p53 as well as number of cell cycle-related genes, which may or may not be directly linked to p53.     

p53 and disease: when the guardian angel fails

The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.     

p53与细胞死亡

p53是一种重要的肿瘤抑制因子,是迄今发现与人类肿瘤相关性最高的分子之一。超过50%的人类肿瘤含有p53基因突变。因此,p53是肿瘤治疗中的重要分子靶点。p53依赖的细胞凋亡是其抑制肿瘤的重要机制之一。然而,最近研究发现,p53不仅参与细胞凋亡,还与程序性细胞坏死、细胞自噬以及铁诱导的细胞死亡等细胞死亡途径相关。促使肿瘤细胞死亡是肿瘤治疗的重要目标。因此,进一步了解p53与细胞死亡之间的关系,将有助于探索以p53为靶点的肿瘤治疗和p53相关肿瘤细胞耐药机制。     

The p53 mutation "gradient effect" and its clinical implications

The p53 tumor suppressor-signaling pathway is inactivated in most human cancers. Depending on how p53 is targeted during tumorigenesis impacts whether partial or full tumor suppressor activity is lost. The degree of remaining p53 activity, if any, intuitively impacts the tumor phenotype. This review focuses on recent findings from human cancer studies and genetically engineered mouse models to highlight a p53 functional "gradient effect" and its clinical implications.     

Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations.

Several lines of evidence suggest that the presence of the wild-type tumor suppressor gene p53 in human cancers correlates well with successful anti-cancer therapy. Restoration of wild-type p53 function to cancer cells that have lost it might therefore improve treatment outcomes. Using a systematic yeast genetic approach, we selected second-site suppressor mutations that can overcome the deleterious effects of common p53 cancer mutations in human cells. We identified several suppressor mutations for the V143A, G245S and R249S cancer mutations. The beneficial effects of these suppressor mutations were demonstrated using mammalian reporter gene and apoptosis assays. Further experiments showed that these suppressor mutations could override additional p53 cancer mutations. The mechanisms of such suppressor mutations can be elucidated by structural studies, ultimately leading to a framework for the discovery of small molecules able to stabilize p53 mutants.