The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury.
The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury.
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DOI：
10.1371/journal.pone.0075483
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Baksh S
中科院分区：
文献类型：
--
作者：
Gordon M;El-Kalla M;Zhao Y;Fiteih Y;Law J;Volodko N;Anwar-Mohamed A;El-Kadi AO;Liu L;Odenbach J;Thiesen A;Onyskiw C;Ghazaleh HA;Park J;Lee SB;Yu VC;Fernandez-Patron C;Alexander RT;Wine E;Baksh S
Ras 关联域家族蛋白 1A (RASSF1A) 是一种在癌症中沉默的抑癌基因。在这里，我们报道 RASSF1A 是肠道炎症的新型调节剂，因为 Rassf1a+/-、Rassf1a−/− 和肠上皮细胞特异性敲除小鼠 (Rassf1a IEC-KO) 在施用右旋糖酐硫酸钠 (DSS)（结肠炎的化学诱导剂）后迅速患病。 Rassf1a 基因敲除小鼠表现出炎症性肠病的临床症状，包括：肠道通透性增加、细胞因子/趋化因子产生增强、B 细胞中 kappa 轻链多肽基因增强子核因子 (NFκB) 活性升高、结肠细胞死亡增加和上皮细胞损伤。此外，在 DSS 处理的 Rassf1a−/− 小鼠中，上皮恢复/修复受到抑制，几个增殖标志物减少，包括 Yes 相关蛋白 (YAP) 驱动的增殖。令人惊讶的是，检测到 YAP 的酪氨酸磷酸化，这与核 p73 关联增加、Bax 驱动的上皮细胞死亡和 p53 积累相一致，导致 DSS 处理的 Rassf1a 敲除小鼠细胞凋亡增强和存活率低。我们可以通过腹腔注射 c-Abl 和 c-Abl 相关蛋白酪氨酸激酶抑制剂伊马替尼/格列卫来抑制这些事件并促进 DSS 治疗的 Rassf1a 敲除小鼠的存活。然而，在 Rassf1a−/− 背景下，p53 积累并未被伊马替尼/格列卫抑制，这揭示了肠道炎症期间 p53 依赖性细胞死亡的重要性。这些观察结果表明，YAP 的酪氨酸磷酸化（驱动 p73 关联和促凋亡基因如 Bax 的上调）和 p53 的积累是 DSS 处理的 Rassf1a−/− 小鼠中炎症诱导损伤的结果。从机制上讲，我们可以检测到 RASSF1A 与近膜 Toll 样受体 (TLR) 成分之间的强烈关联，表明 RASSF1A 可能具有干扰和限制 TLR 驱动的 NFκB 激活的功能。未能限制 NFκB 会导致炎症诱导的 DNA 损伤，导致 YAP 酪氨酸磷酸化，随后 p53 积累和肠上皮稳态丧失。
Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a+/−, Rassf1a−/− and an intestinal epithelial cell specific knockout mouse (Rassf1a IEC-KO) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a−/− mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a−/− background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS-treated Rassf1a−/− mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR-driven activation of NFκB. Failure to restrict NFκB resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis.
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影响因子：
13.5
作者：
Braconi, Chiara;Huang, Nianyuan;Patel, Tushar
通讯作者：
Patel, Tushar
DOI：
10.1038/nrgastro.2010.39
发表时间：
2010-05
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
8
作者：
Allen, N. P. C.;Donninger, H.;Clark, G. J.
通讯作者：
Clark, G. J.
影响因子：
5.5
作者：
Anwar, Adil;Keating, Amy K.;Graham, Douglas K.
通讯作者：
Graham, Douglas K.
影响因子：
16
作者：
Baksh, S;Widlund, HR;Burakoff, SJ
通讯作者：
Burakoff, SJ