Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Mol Cell. 2009 Dec 11;36(5):754-67. doi: 10.1016/j.molcel.2009.09.044.
SOCS1 is lost in many human tumors, but its tumor suppression activities are not well understood. We report that SOCS1 is required for transcriptional activity, DNA binding, and serine 15 phosphorylation of p53 in the context of STAT5 signaling. In agreement, inactivation of SOCS1 disabled p53-dependent senescence in response to oncogenic STAT5A and radiation-induced apoptosis in T cells. In addition, SOCS1 was sufficient to induce p53-dependent senescence in fibroblasts. The mechanism of activation of p53 by SOCS1 involved a direct interaction between the SH2 domain of SOCS1 and the N-terminal transactivation domain of p53, while the C-terminal domain of SOCS1 containing the SOCS Box mediated interaction with the DNA damage-regulated kinases ATM/ATR. Also, SOCS1 colocalized with ATM at DNA damage foci induced by oncogenic STAT5A. Collectively, these results add another component to the p53 and DNA damage networks and reveal a mechanism by which SOCS1 functions as a tumor suppressor.
SOCS1 在许多人类肿瘤中丢失，但它的肿瘤抑制活性尚不清楚。我们报告 SOCS1 在 STAT5 信号通路中 p53 的转录活性、DNA 结合和丝氨酸 15 磷酸化是必需的。一致地，SOCS1 的失活使 T 细胞中的癌基因 STAT5A 和辐射诱导的凋亡不能引起 p53 依赖性衰老。此外，SOCS1 足以诱导成纤维细胞中的 p53 依赖性衰老。SOCS1 通过直接相互作用 SOCS1 的 SH2 结构域和 p53 的 N 端转录激活域来激活 p53，而含有 SOCS 盒的 SOCS1 的 C 端结构域介导与 DNA 损伤调节激酶 ATM/ATR 的相互作用。此外，SOCS1 在癌基因 STAT5A 诱导的 DNA 损伤焦点处与 ATM 共定位。总之，这些结果为 p53 和 DNA 损伤网络添加了另一个组成部分，并揭示了 SOCS1 作为肿瘤抑制因子的作用机制。
