抑癌基因 TP53 在调控细胞周期、细胞凋亡和维持基因组稳定的过程中发挥着重要作用。 TP63 和 TP73 是 TP53 家族中包含的另外两个成员,均具有多种亚型,这些亚型通过自身家族或与其它转录因子家族之 间的相互作用,从而对广泛的基因群发挥调控作用。 本文将综述 TP53 及其家族成员 TP63、TP73 的功能学研究 上的最新进展,并将重点介绍我们 NIH/ NIDCD 头颈外科实验室的近期的研究工作所取得的新发现。 我们近期 的研究结果揭示了在肿瘤炎症的微环境中,存在着一种新的可逆转的动态机制为促炎症细胞因子 TNF-琢 诱导 NF-资B c-REL/ 驻Np 63琢 相互作用,协同促进细胞增殖、生存、炎症和迁移相关基因群的调控。 并在有突变的 TP53 肿瘤中,这些相互作用同时使肿瘤抑制基因 TAp73 的功能失活,促进肿瘤对 TNF-琢 的抗药性和细胞生存。 我们的研究阐述了炎症与肿瘤发生、发展的新机制,其中 NF-资B 和 TP53 两大转录因子家族基因的相互作用起 到了关键性作用。 这一新发现或许可为肿瘤的诊断、治疗和预防提供新的策略。

As a tumor suppressor, TP53 plays a crucial role in the cell cycle, apoptosis, and genome stability. DNA-damaging agents activate the TP53 signaling pathway and lead cells either in cell cycle arrest to allow DNA repair,or induce cell apoptosis. The rate of TP53 mutation is extremely high in cancer,so that it not only abrogates TP53 tumor-suppressive functions,but may also alter or gain functions to promote oncogenesis. TP53 has other family members,including TP63 and TP73,and their isoforms are capable of regulating a broad gene programs,primarily through interactions within their family members, or with other transcription factors families. In this review, we summarize the current knowledge of TP53,TP63 and TP73 family members,and highlight recent novel findings from our laboratory (Head and Neck Surgery Branch,National Institute on Deafness and CommunicationDisorders, National Institutes of Health ). Our findings unveil a novel and reversible dynamic mechanism in the inflammatory tumor microenvironment,whereby proinflammatory cytokine TNF - 琢 induces NF-kB c-REL / 驻Np 63琢 interactions to promote a broad gene program involved in cell prolif鄄 eration,survival,inflammation and migration. This interaction also inhibits tumor suppressor TAp 73 function,promoting TNF -琢 resistance and cell survival in cancers with mutant TP53. Our findings provide a novel connection between inflammation and cancer survival through two families of transcription factors, TP53 and NF - kB, which may lead to a new strategy for cancer prevention, diagnostics and therapy.

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