Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling.
Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling.
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DOI：
10.1016/j.devcel.2010.07.015
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发表时间：
2010-08-17
影响因子：
11.8
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
--
作者：
Ashton, Gabrielle H.;Morton, Jennifer P.;Myant, Kevin;Phesse, Toby J.;Ridgway, Rachel A.;Marsh, Victoria;Wilkins, Julie A.;Athineos, Dimitris;Muncan, Vanesa;Kemp, Richard;Neufeld, Kristi;Clevers, Hans;Brunton, Valerie;Winton, Douglas J.;Wang, Xiaoyan;Sears, Rosalie C.;Clarke, Alan R.;Frame, Margaret C.;Sansom, Owen J.
肠上皮在损伤和DNA损伤后具有显著的再生能力。在这里，我们表明，整合素效应蛋白粘着斑激酶（FAK）是正常的肠道稳态和DNA损伤信号，但DNA损伤后的肠道再生是必不可少的。鉴于Wnt/c-Myc信号在肠再生后被激活，我们研究了FAK在肠上皮内Apc肿瘤抑制蛋白缺失后的功能重要性。Apc丧失后，FAK表达以c-Myc依赖性方式增加。Apc和Fak的共缺失强烈降低了Apc丢失后正常诱导的增殖，这与Apc杂合子小鼠中磷酸化Akt水平降低和肠道肿瘤发生抑制有关。因此，FAK是Wnt信号传导下游所需的，用于Akt/mTOR活化、肠再生和肿瘤发生。重要的是，这项工作表明，FAK抑制剂可能会抑制结直肠癌高危患者的肿瘤发生。
The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.
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肠上皮中β1整联蛋白的条件缺失会导致刺猬表达，肠道增生和早期产后致死性的丧失。
影响因子：
7.8
作者：
Jones, Robert G.;Li, Xiufen;Gray, Phillip D.;Kuang, Jinqiu;Clayton, Frederic;Samowitz, Wade S.;Madison, Blair B.;Gumucio, Deborah L.;Kuwada, Scott K.
通讯作者：
Kuwada, Scott K.
影响因子：
4.6
作者：
Andreu, P;Colnot, S;Romagnolo, B
通讯作者：
Romagnolo, B
影响因子：
16
作者：
Lim, Ssang-Taek;Chen, Xiao Lei;Llic, Dusko
通讯作者：
Llic, Dusko
影响因子：
8
作者：
Essayem, S;Kovacic-Milivojevic, B;Ilic, D
通讯作者：
Ilic, D
影响因子：
4.7
作者：
Bach, SP;Renehan, AG;Potten, CS
通讯作者：
Potten, CS