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SOCS3 regulates p21 expression and cell cycle arrest in response to DNA damage

机译：SOCS3调节p21表达并响应DNA损伤而抑制细胞周期

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摘要

Genotoxic agents such as ionizing radiation trigger cell cycle arrest at the G1/S and G2/M checkpoints, allowing cells to repair damaged DNA before entry into mitosis. DNA damage-induced G1 arrest involves p53-dependent expression of p21 (Cip1/Waf-1), which inhibits cyclin-dependent kinases and blocks S phase entry. While much of the core DNA damage response has been well-studied, other signaling proteins that intersect with and modulate this response remain uncharacterized. In this study, we identify Suppressor of Cytokine Signaling (SOCS)-3 as an important regulator of radiation-induced G1 arrest. SOCS3-deficient fibroblasts fail to undergo G1 arrest and accumulate in the G2/M phase of the cell cycle. SOCS3 knockout cells phosphorylate p53 and H2AX normally in response to radiation, but fail to upregulate p21 expression. In addition, STAT3 phosphorylation is elevated in SOCS3-deficient cells compared to WT cells. Normal G1 arrest can be restored in SOCS3 KO cells by retroviral transduction of WT SOCS3 or a dominant-negative mutant of STAT3. Our results suggest a novel function for SOCS3 in the control of genome stability by negatively regulating STAT3-dependent radioresistant DNA synthesis, and promoting p53-dependent p21 expression. Published by Elsevier Inc.
机译：诸如电离辐射之类的基因毒性剂会触发细胞周期停滞在G1 / S和G2 / M检查点，从而使细胞能够在进入有丝分裂之前修复受损的DNA。 DNA损伤诱导的G1阻滞涉及p21依赖于p53的表达（Cip1 / Waf-1），它抑制细胞周期蛋白依赖性激酶并阻止S期进入。尽管已经对许多核心DNA损伤反应进行了深入研究，但与该反应相交并调节该反应的其他信号蛋白仍未表征。在这项研究中，我们确定细胞因子信号转导抑制因子（SOCS）-3是辐射诱导的G1阻滞的重要调节剂。缺乏SOCS3的成纤维细胞无法进行G1阻滞并在细胞周期的G2 / M期积聚。 SOCS3敲除细胞正常情况下会响应辐射使p53和H2AX磷酸化，但不能上调p21表达。另外，与WT细胞相比，SOCS3缺陷型细胞中STAT3磷酸化升高。可以通过逆转录病毒转导WT SOCS3或STAT3的显性负突变来在SOCS3 KO细胞中恢复正常的G1阻滞。我们的结果表明，通过负调节STAT3依赖的抗辐射性DNA合成并促进p53依赖的p21表达，SOCS3在控制基因组稳定性方面具有新颖的功能。由Elsevier Inc.发布

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