Petrova Varvara, Mancini Mara, Agostini Massimiliano, Knight Richard A, Annicchiarico-Petruzzelli Margherita, Barlev Nikolai A, Melino Gerry, Amelio Ivano
a Medical Research Council; Toxicology Unit; Leicester University ; Leicester , UK.
Cell Cycle. 2015 Aug 3;14(15):2484-93. doi: 10.1080/15384101.2015.1044178.
TAp73 is a tumor suppressor transcriptional factor, belonging to p53 family. Alteration of TAp73 in tumors might lead to reduced DNA damage response, cell cycle arrest and apoptosis. Carcinogen-induced TAp73(-/-) tumors display also increased angiogenesis, associated to hyperactivition of hypoxia inducible factor signaling. Here, we show that TAp73 suppresses BNIP3 expression, directly binding its gene promoter. BNIP3 is a hypoxia responsive protein, involved in a variety of cellular processes, such as autophagy, mitophagy, apoptosis and necrotic-like cell death. Therefore, through different cellular process altered expression of BNIP3 may differently contribute to cancer development and progression. We found a significant upregulation of BNIP3 in human lung cancer datasets, and we identified a direct association between BNIP3 expression and survival rate of lung cancer patients. Our data therefore provide a novel transcriptional target of TAp73, associated to its antagonistic role on HIF signaling in cancer, which might play a role in tumor suppression.
TAp73是一种肿瘤抑制转录因子，属于p53家族。肿瘤中TAp73的改变可能导致DNA损伤反应、细胞周期停滞和细胞凋亡减少。致癌物诱导的TAp73(-/-)肿瘤还表现出血管生成增加，这与缺氧诱导因子信号的过度激活有关。在此，我们表明TAp73通过直接结合其基因启动子来抑制BNIP3的表达。BNIP3是一种缺氧反应蛋白，参与多种细胞过程，如自噬、线粒体自噬、细胞凋亡和坏死样细胞死亡。因此，通过不同的细胞过程，BNIP3表达的改变可能对癌症的发生和发展有不同的影响。我们发现人类肺癌数据集中BNIP3有显著上调，并且我们确定了BNIP3表达与肺癌患者生存率之间存在直接关联。因此，我们的数据提供了TAp73的一个新的转录靶点，与其在癌症中对HIF信号的拮抗作用相关，这可能在肿瘤抑制中发挥作用。
