Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis
Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis
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DOI：
10.1158/0008-5472.can-06-3558
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Jones, Stephen N.
中科院分区：
文献类型：
--
作者：
Coles, Andrew H.;Liang, Huiling;Jones, Stephen N.
ING蛋白已被提出改变染色质结构和基因转录以调节细胞生理学的许多方面，包括细胞生长、衰老、应激反应、凋亡和转化。ING1是生长抑制因子家族的创始成员，编码p371（Ing1），这是一种与p53肿瘤抑制蛋白相互作用的植物同源域（PHD）蛋白，并且似乎是p53介导的细胞生长和凋亡调节的关键辅因子。在这项研究中，我们已经产生并分析了p37（Ing1）缺陷小鼠和原代细胞，以进一步探索Ing1在细胞生长和p53活性调节中的作用。结果表明，内源性水平的p37（Ing1），抑制p53野生型和p53缺陷型成纤维细胞的增殖，并在p37（Ing1）缺陷型细胞中p53功能不受干扰。此外，在原代细胞和小鼠中，p37（Ing1）的缺失诱导Bax表达并增加DNA损伤诱导的凋亡，而与p53状态无关。最后，p37（Ing1）抑制小鼠自发性滤泡B细胞淋巴瘤的形成。这些结果表明，P53不需要p37（Ing1）来负调节细胞生长，并提供了Ing1抑制细胞生长和肿瘤发生的遗传证据。此外，这些数据表明，p37（Ing1）可以负调控细胞的生长和凋亡的p53非依赖性的方式。
ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p371(Ing1), a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37(Ing1)-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity. The results show that endogenous levels of p37(Ing1), inhibit the proliferation of p53-wild-type and p53-deficient fibroblasts, and that p53 functions are unperturbed in p37(Ing1)-deficient cells. In addition, loss of p37(Ing1) induces Bax expression and increases DNA damage-induced apoptosis in primary cells and mice irrespective of p53 status. Finally, p37(Ing1) suppresses the formation of spontaneous follicular B-cell lymphomas in mice. These results indicate that P53 does not require p37(Ing1) to negatively regulate cell growth and offers genetic proof that Ing1 suppresses cell growth and tumorigenesis. Furthermore, these data reveal that p37(Ing1) can negatively regulate cell growth and apoptosis in a p53-independent manner.