Zhang Ying, Dube Collin, Gibert Myron, Cruickshanks Nichola, Wang Baomin, Coughlan Maeve, Yang Yanzhi, Setiady Initha, Deveau Ciana, Saoud Karim, Grello Cassandra, Oxford Madison, Yuan Fang, Abounader Roger
Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
Cancers (Basel). 2018 Sep 1;10(9):297. doi: 10.3390/cancers10090297.
The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment. is one of the most commonly deregulated genes in cancer. The p53-ARF-MDM2 pathway is deregulated in 84% of glioblastoma (GBM) patients and 94% of GBM cell lines. Deregulated p53 pathway components have been implicated in GBM cell invasion, migration, proliferation, evasion of apoptosis, and cancer cell stemness. These pathway components are also regulated by various microRNAs and long non-coding RNAs. mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein. These relatively understudied GOF p53 mutants promote GBM malignancy, possibly by acting as transcription factors on a set of genes other than those regulated by wild type p53. Their expression correlates with worse prognosis, highlighting their potential importance as markers and targets for GBM therapy. Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies.
肿瘤抑制因子和转录因子p53通过协调多种细胞反应在肿瘤预防中发挥关键作用，这些反应包括受损细胞凋亡、基因组稳定性维持、血管生成抑制以及细胞代谢和肿瘤微环境调节。它是癌症中最常失调的基因之一。在84%的胶质母细胞瘤（GBM）患者和94%的GBM细胞系中，p53-ARF-MDM2通路失调。失调的p53通路成分与GBM细胞的侵袭、迁移、增殖、凋亡逃避和癌细胞干性有关。这些通路成分也受各种微小RNA和长链非编码RNA的调控。GBM中的突变大多是点突变，导致p53蛋白功能获得性（GOF）致癌变体的高表达。这些相对较少研究的GOF p53突变体可能通过作为一组不同于野生型p53调控基因的转录因子来促进GBM的恶性发展。它们的表达与较差的预后相关，突出了它们作为GBM治疗标志物和靶点的潜在重要性。对突变型p53功能的理解导致了恢复p53活性或促进突变型p53降解的新方法的开发，用于未来的GBM治疗。
