Instituto de Biomedicina (IBIOMED), Department of Molecular Biology, Universidad de León, Campus de Vegazana, León 24071, Spain.
Cell Death Dis. 2013 Jul 4;4(7):e704. doi: 10.1038/cddis.2013.224.
The p73 transcription factor is one of the members of the p53 family of tumor suppressors with unique biological functions in processes like neurogenesis, embryonic development and differentiation. For this reason, p73 activity is tightly regulated by multiple mechanisms, including transcription and post-translational modifications. Here, we identified a novel regulatory loop between TAp73 and the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32). TRIM32, a new direct p73 transcriptional target in the context of neural progenitor cells, is differentially regulated by p73. Although TAp73 binds to the TRIM32 promoter and activates its expression, TAp73-induced TRIM32 expression is efficiently repressed by DNp73. TRIM32 in turn physically interacts with TAp73 and promotes its ubiquitination and degradation, impairing p73-dependent transcriptional activity. This mutual regulation between p73 and TRIM32 constitutes a novel feedback loop, which might have important implications in central nervous system development as well as relevance in oncogenesis, and thus emerges as a possible therapeutic target.
p73 转录因子是肿瘤抑制因子 p53 家族的成员之一，在神经发生、胚胎发育和分化等过程中具有独特的生物学功能。因此，p73 的活性受到多种机制的严格调节，包括转录和翻译后修饰。在这里，我们在神经祖细胞中发现了 TAp73 和 E3 泛素连接酶三部分基序蛋白 32（TRIM32）之间的一个新的调节环。TRIM32 是 p73 的一个新的直接转录靶标，在不同的条件下受到 p73 的调节。虽然 TAp73 结合到 TRIM32 的启动子并激活其表达，但 DNp73 有效地抑制了 TAp73 诱导的 TRIM32 表达。反过来，TRIM32 与 TAp73 相互作用，并促进其泛素化和降解，从而损害了 p73 依赖性转录活性。p73 和 TRIM32 之间的这种相互调节构成了一个新的反馈环，这可能对中枢神经系统的发育以及肿瘤发生具有重要意义，并因此成为一个可能的治疗靶点。
