The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury

被引：41

作者：

Gordon, Marilyn ^{[1
]}

El-Kalla, Mohamed ^{[1
]}

Zhao, Yuewen ^{[2
]}

Fiteih, Yahya ^{[1
]}

Law, Jennifer ^{[2
]}

Volodko, Natalia ^{[1
]}

Mohamed, Anwar ^{[3
]}

El-Kadi, Ayman O. S. ^{[3
]}

Liu, Lei ^{[4
]}

Odenbach, Jeff ^{[2
]}

Thiesen, Aducio ^{[5
]}

Onyskiw, Christina ^{[1
]}

Abu Ghazaleh, Haya ^{[1
]}

Park, Jikyoung ^{[6
]}

Lee, Sean Bong ^{[6
]}

Yu, Victor C. ^{[7
]}

Fernandez-Patron, Carlos ^{[2
]}

Alexander, R. Todd ^{[1
,8
]}

Wine, Eytan ^{[1
,4
,9
]}

Baksh, Shairaz ^{[1
,2
,9
]}

机构：

[1] Univ Alberta, Dept Pediat, Edmonton, AB, Canada

[2] Univ Alberta, Dept Biochem, Edmonton, AB, Canada

[3] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada

[4] Univ Alberta, Fac Med & Dent, CEGIIR, Edmonton, AB, Canada

[5] Univ Alberta, Dept Lab Med & Pathol, Fac Med & Dent, Edmonton, AB, Canada

[6] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA

[7] Natl Univ Singapore, Dept Pharm, Fac Sci, Singapore 117548, Singapore

[8] Univ Alberta, Dept Nephrol, Edmonton, AB, Canada

[9] Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada

来源：

PLOS ONE | 2013年 / 8卷 / 10期

基金：

加拿大健康研究院;

关键词：

YES-ASSOCIATED PROTEIN; STEM-CELL PROLIFERATION; NF-KAPPA-B; C-ABL; DNA METHYLTRANSFERASE-1; YAP; P53; APOPTOSIS; PROMOTES; PHOSPHORYLATION;

D O I：

10.1371/journal.pone.0075483

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 (NF kappa B) 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 NF kappa B. Failure to restrict NF kappa B resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis.

引用

页数：21

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