The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)
The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)
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DOI：
10.1073/pnas.0502716102
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发表时间：
2005-05-24
影响因子：
11.1
通讯作者：
Bruick, RK
中科院分区：
文献类型：
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作者：
Ozer, A;Wu, LC;Bruick, RK
缺氧诱导因子（hypoxia inducible factor，HIF）在肿瘤发生等多种病理生理过程中起重要作用。除了几种充分表征的氧依赖性调节模式之外，HIF转录因子的功能也可以通过其他调节途径的作用而受到影响。这些因子的失调导致不适当的HIF表达或活性，可通过诱导促进血管生成、糖酵解、细胞存活和转移等过程的基因而促进人类癌症的进展。候选肿瘤抑制蛋白生长家族成员抑制剂4（ING 4）最近被认为是通过与NF-κ B相关的血管生成和肿瘤生长的抑制剂。在这里，我们证明了ING 4的抑制进一步诱导HIF转录活性。ING 4直接与HIF脯氨酰羟化酶相关，这是一种Fe（II）依赖性加氧酶，以前显示出介导HIF稳定性作为氧可用性的函数。然而，ING 4并不影响HIF的稳定性，而是介导HIF的活性。这些数据支持一个模型，其中，除了调节HIF稳定性，HIF脯氨酰羟化酶可以调节HIF功能通过招聘ING 4，一个可能的组成部分，染色质重塑复合物。
The hypoxia inducible factor (HIF) plays an important role in the progression of a number of pathophysiological processes including tumorigenesis. In addition to several well characterized oxygen-dependent modes of regulation, the function of the HIF transcription factor can also be influenced through the action of other regulatory pathways. Misregulation of these factors resulting in inappropriate HIF expression or activity can contribute to the progression of human cancers through the induction of genes promoting angiogenesis, glycolysis, cell survival, and metastasis, among other processes. The candidate tumor suppressor protein inhibitor of growth family member 4 (ING4) has recently been implicated as a repressor of angiogenesis and tumor growth through association with NF-kappa B. Here we demonstrate that suppression of ING4 further induces HIF transcriptional activity as well. ING4 directly associates with the HIF prolyl hydroxylase, an Fe(II)-dependent oxygenase previously shown to mediate HIF stability as a function of oxygen availability. However, rather than affecting HIF's stability, ING4 mediates HIF's activity. These data support a model in which, in addition to regulating HIF stability, HIF prolyl hydroxylases can modulate HIF function through the recruitment of ING4, a likely component of a chromatin-remodeling complex.