Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling

被引:162
作者
Ashton, Gabrielle H. [1 ]
Morton, Jennifer P. [1 ]
Myant, Kevin [1 ]
Phesse, Toby J. [2 ]
Ridgway, Rachel A. [1 ]
Marsh, Victoria [2 ]
Wilkins, Julie A. [1 ]
Athineos, Dimitris [1 ]
Muncan, Vanesa [3 ,4 ]
Kemp, Richard [5 ]
Neufeld, Kristi [6 ]
Clevers, Hans [3 ,4 ]
Brunton, Valerie [7 ]
Winton, Douglas J. [5 ]
Wang, Xiaoyan [8 ]
Sears, Rosalie C. [8 ]
Clarke, Alan R. [2 ]
Frame, Margaret C. [7 ]
Sansom, Owen J. [1 ]
机构
[1] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
[2] Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales
[3] Royal Netherlands Acad Arts & Sci, Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands
[4] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands
[5] CIMR, CR UK Dept Oncol, Cambridge CB2 2XY, England
[6] Univ Kansas, Lawrence, KS 66045 USA
[7] Univ Edinburgh, IGMM, Edinburgh Canc Res UK Ctr, Edinburgh EH4 2XR, Midlothian, Scotland
[8] Oregon Hlth & Sci Univ, Portland, OR 97239 USA
关键词
EPITHELIAL-SPECIFIC DISRUPTION; STEM-CELLS; IN-VIVO; C-MYC; CONDITIONAL DELETION; APC DEFICIENCY; CANCER-CELLS; TUMOR PROGRESSION; INDUCED APOPTOSIS; MOUSE INTESTINE;
D O I
10.1016/j.devcel.2010.07.015
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:259 / 269
页数:11
相关论文
共 55 条
[1]   Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells [J].
Agochiya, M ;
Brunton, VG ;
Owens, DW ;
Parkinson, EK ;
Paraskeva, C ;
Keith, WN ;
Frame, MC .
ONCOGENE, 1999, 18 (41) :5646-5653
[2]   Inhibition of Mammalian Target of Rapamycin by Rapamycin Causes the Regression of Carcinogen-induced Skin Tumor Lesions [J].
Amornphimoltham, Panomwat ;
Leelahavanichkul, Kantima ;
Molinolo, Alfredo ;
Patel, Vyomesh ;
Gutkind, J. Silvio .
CLINICAL CANCER RESEARCH, 2008, 14 (24) :8094-8101
[3]   Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine [J].
Andreu, P ;
Colnot, S ;
Godard, C ;
Gad, S ;
Chafey, P ;
Niwa-Kawakita, M ;
Laurent-Puig, P ;
Kahn, A ;
Robine, S ;
Perret, C ;
Romagnolo, B .
DEVELOPMENT, 2005, 132 (06) :1443-1451
[4]   Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine [J].
Athineos, D. ;
Sansom, O. J. .
ONCOGENE, 2010, 29 (17) :2585-2590
[5]   Stem cells: the intestinal stem cell as a paradigm [J].
Bach, SP ;
Renehan, AG ;
Potten, CS .
CARCINOGENESIS, 2000, 21 (03) :469-476
[6]   c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver [J].
Baena, E ;
Gandarillas, A ;
Vallespinós, M ;
Zanet, J ;
Bachs, O ;
Redondo, C ;
Fabregat, I ;
Martinez, C ;
de Alborán, IM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (20) :7286-7291
[7]   The intestinal stem cell [J].
Barker, Nick ;
van de Wetering, Marc ;
Clevers, Hans .
GENES & DEVELOPMENT, 2008, 22 (14) :1856-1864
[8]   Identification of stem cells in small intestine and colon by marker gene Lgr5 [J].
Barker, Nick ;
van Es, Johan H. ;
Kuipers, Jeroen ;
Kujala, Pekka ;
van den Born, Maaike ;
Cozijnsen, Miranda ;
Haegebarth, Andrea ;
Korving, Jeroen ;
Begthel, Harry ;
Peters, Peter J. ;
Clevers, Hans .
NATURE, 2007, 449 (7165) :1003-U1
[9]   Crypt stem cells as the cells-of-origin of intestinal cancer [J].
Barker, Nick ;
Ridgway, Rachel A. ;
van Es, Johan H. ;
van de Wetering, Marc ;
Begthel, Harry ;
van den Born, Maaike ;
Danenberg, Esther ;
Clarke, Alan R. ;
Sansom, Owen J. ;
Clevers, Hans .
NATURE, 2009, 457 (7229) :608-U119
[10]   N-MYC regulates focal adhesion kinase expression in human neuroblastoma [J].
Beierle, Elizabeth A. ;
Trujillo, Angelica ;
Nagaram, Abhilasha ;
Kurenova, Elena V. ;
Finch, Richard ;
Ma, Xiaojie ;
Vella, Jennifer ;
Cance, William G. ;
Golubovskaya, Vita M. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (17) :12503-12516