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首页> 外文期刊>Cell cycle >Hypoxia-induced DNp73 stabilization regulates Vegf-A expression and tumor angiogenesis similar to TAp73
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Hypoxia-induced DNp73 stabilization regulates Vegf-A expression and tumor angiogenesis similar to TAp73

机译：低氧诱导的DNp73稳定调节Vegf-A表达和类似于TAp73的肿瘤血管生成

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摘要

P73, the homolog of p53, exists in 2 major forms: either as a pro-apoptotic TAp73 or an amino-terminally truncated DNp73, the latter lacking the first transactivation domain. While TAp73s tumor suppressive functions have been established, DNp73 is an anti-apoptotic protein conferring chemoresistance and is associated with poor survival. However, both forms are variably overexpressed in many human cancers. In this context, we have recently demonstrated that TAp73 is stabilized by hypoxia, a tumor-relevant condition that is associated with cell survival, via HIF-1-mediated suppression of Siah1 E3 ligase that degrades TAp73. Consequently, hypoxic signals lead to TAp73-mediated activation of several angiogenic genes and blood vessel formation, thereby supporting tumorigenesis. We show here that, similar to TAp73, DNp73 is stabilized by hypoxia in a HIF-1-dependent manner, which otherwise is degraded by Siah1. Moreover, DNp73 is capable of inducing the expression of Vegf-A, the prototypic angiogenic gene, and loss of DNp73 expression results in reduction in tumor vasculature and size. These data therefore indicate a common mode of regulation for both p73 forms by hypoxia, resulting in the promotion of angiogenesis and tumor growth, highlighting common functionality of these antagonistic proteins under specific physiological contexts.
机译：P73是p53的同源物，以2种主要形式存在：以促凋亡TAp73或氨基末端截短的DNp73形式存在，后者缺少第一个反式激活结构域。虽然已经建立了TAp73s的肿瘤抑制功能，但DNp73是一种抗凋亡蛋白，具有化学耐药性，并且与较差的存活率有关。但是，两种形式在许多人类癌症中都有不同程度的过表达。在这种情况下，我们最近证明，通过HIF-1介导的抑制降解TAp73的Siah1 E3连接酶的抑制，TAp73被缺氧所稳定，这是一种与细胞存活相关的肿瘤相关疾病。因此，低氧信号导致TAp73介导的几个血管生成基因的激活和血管形成，从而支持肿瘤发生。我们在这里显示，与TAp73相似，DNp73通过缺氧以HIF-1依赖的方式稳定，否则被Siah1降解。此外，DNp73能够诱导原型血管生成基因Vegf-A的表达，并且DNp73表达的丧失导致肿瘤脉管系统和大小的减少。因此，这些数据表明了通过缺氧对两种p73形式进行调节的共同模式，从而促进了血管生成和肿瘤生长，突出了这些拮抗蛋白在特定生理环境下的共同功能。

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