Ory Benjamin, Ellisen Leif W
Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.
Oncotarget. 2011 Mar;2(3):259-64. doi: 10.18632/oncotarget.244.
The p53 family transcription factors p53, p63 and p73 make diverse contributions in development and cancer. Mutation or deletion of p53 is observed in the majority of human cancers. In contrast, p63 and p73 are not lost in cancer but mediate distinct genetic roles in normal and tumor-specific contexts: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. We recently uncovered a mechanism which maintains p63/p73 homeostasis within the epithelium through direct transcriptional regulation of microRNAs (miRs). We discovered that several of the top p63-regulated miRs target p73 for inhibition, including miR-193a-5p, a direct p63/p73 transcriptional target which is repressed by p63 and activated by p73 both in vitro and in vivo. The resulting feed-forward circuit involving p63, miR-193a-5p and p73 controls p73 levels, cell viability and DNA damage susceptibility in certain cancers including squamous cell carcinoma. Here, we discuss the evolutionary implications of this regulatory circuit, which may point to a general mechanism of miR-mediated cross-talk within transcription factor gene families. Additionally, we suggest that inducible chemoresistance mediated by this miR-dependent mechanism might be an attractive target for therapeutic intervention.
p53家族转录因子p53、p63和p73在发育和癌症中发挥着不同的作用。在大多数人类癌症中都观察到p53的突变或缺失。相比之下，p63和p73在癌症中并未缺失，但在正常和肿瘤特异性环境中介导不同的遗传作用：p73促进基因组稳定性并介导化学敏感性，而p63在很大程度上缺乏这些类似p53的功能，反而促进增殖和细胞存活。我们最近发现了一种机制，该机制通过对微小RNA（miR）的直接转录调控来维持上皮细胞内p63/p73的稳态。我们发现，几个受p63高度调控的miR靶向抑制p73，包括miR-193a-5p，它是p63/p73的直接转录靶点，在体外和体内均受p63抑制并被p73激活。由此产生的涉及p63、miR-193a-5p和p73的前馈回路控制着某些癌症（包括鳞状细胞癌）中的p73水平、细胞活力和DNA损伤易感性。在这里，我们讨论了这种调控回路的进化意义，它可能指向转录因子基因家族内miR介导的相互作用的一般机制。此外，我们认为由这种miR依赖性机制介导的诱导性化疗耐药性可能是治疗干预的一个有吸引力的靶点。
