The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor

被引：628

作者：

Powell, Anne E. ^{[1
,2
]}

Wang, Yang ^{[1
,2
]}

Li, Yina ^{[1
,2
]}

Poulin, Emily J. ^{[1
,2
]}

Means, Anna L. ^{[3
]}

Washington, Mary K. ^{[4
]}

Higginbotham, James N. ^{[1
,2
]}

Juchheim, Alwin ^{[7
,8
]}

Prasad, Nripesh ^{[9
]}

Levy, Shawn E. ^{[9
]}

Guo, Yan ^{[5
]}

Shyr, Yu ^{[5
]}

Aronow, Bruce J. ^{[10
,11
]}

Haigis, Kevin M. ^{[7
,8
]}

Franklin, Jeffrey L. ^{[1
,2
]}

Coffey, Robert J. ^{[1
,2
,6
,12
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Med Ctr, Epithelial Biol Ctr, Nashville, TN 37232 USA

[7] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Pathol Unit, Charlestown, MA 02129 USA

[8] Harvard Univ, Sch Med, Dept Pathol, Charlestown, MA 02129 USA

[9] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

[10] Cincinnati Childrens Hosp, Med Ctr, Dept Biomed Informat, Cincinnati, OH 45229 USA

[11] Cincinnati Childrens Hosp, Med Ctr, Dept Dev Biol, Cincinnati, OH 45229 USA

[12] Dept Vet Affairs Med Ctr, Nashville, TN 37232 USA

来源：

CELL | 2012年 / 149卷 / 01期

关键词：

IMMUNOHISTOCHEMICAL ANALYSIS; OXIDATIVE STRESS; EXPRESSION MARKS; CANCER; RECEPTOR; GENE; PROLIFERATION; GROWTH; CRYPTS; POPULATION;

D O I：

10.1016/j.cell.2012.02.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1(+) colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5(+) colonic stem cells; genes upregulated in the Lrig1(+) population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1(+) cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by calibrated ErbB signaling with loss of a negative regulator predisposing to neoplasia.

引用

页码：146 / 158

页数：13

共 49 条

[1]

AKASHI T, 1994, VIRCHOWS ARCH, V425, P399

[2]

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

[3]

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

[4]

Accurate whole human genome sequencing using reversible terminator chemistry [J].

Bentley, David R. ;

Balasubramanian, Shankar ;

Swerdlow, Harold P. ;

Smith, Geoffrey P. ;

Milton, John ;

Brown, Clive G. ;

Hall, Kevin P. ;

Evers, Dirk J. ;

Barnes, Colin L. ;

Bignell, Helen R. ;

Boutell, Jonathan M. ;

Bryant, Jason ;

Carter, Richard J. ;

Cheetham, R. Keira ;

Cox, Anthony J. ;

Ellis, Darren J. ;

Flatbush, Michael R. ;

Gormley, Niall A. ;

Humphray, Sean J. ;

Irving, Leslie J. ;

Karbelashvili, Mirian S. ;

Kirk, Scott M. ;

Li, Heng ;

Liu, Xiaohai ;

Maisinger, Klaus S. ;

Murray, Lisa J. ;

Obradovic, Bojan ;

Ost, Tobias ;

Parkinson, Michael L. ;

Pratt, Mark R. ;

Rasolonjatovo, Isabelle M. J. ;

Reed, Mark T. ;

Rigatti, Roberto ;

Rodighiero, Chiara ;

Ross, Mark T. ;

Sabot, Andrea ;

Sankar, Subramanian V. ;

Scally, Aylwyn ;

Schroth, Gary P. ;

Smith, Mark E. ;

Smith, Vincent P. ;

Spiridou, Anastassia ;

Torrance, Peta E. ;

Tzonev, Svilen S. ;

Vermaas, Eric H. ;

Walter, Klaudia ;

Wu, Xiaolin ;

Zhang, Lu ;

Alam, Mohammed D. ;

Anastasi, Carole .

NATURE, 2008, 456 (7218) :53-59

[5]

Cai WB, 1997, INT J RADIAT BIOL, V71, P573, DOI 10.1080/095530097143905

[6]

Clarke Michael F, 2006, Cancer Res, V66, P9339, DOI 10.1158/0008-5472.CAN-06-3126

[7]

Inflammation and Proliferation Act Together to Mediate Intestinal Cell Fusion [J].

Davies, Paige S. ;

Powell, Anne E. ;

Swain, John R. ;

Wong, Melissa H. .

PLOS ONE, 2009, 4 (08)

[8]

Intestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation [J].

Escobar, Marion ;

Nicolas, Pierre ;

Sangar, Fatiha ;

Laurent-Chabalier, Sabine ;

Clair, Philippe ;

Joubert, Dominique ;

Jay, Philippe ;

Legraverend, Catherine .

NATURE COMMUNICATIONS, 2011, 2

[9]

Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains [J].

Feil, R ;

Wagner, J ;

Metzger, D ;

Chambon, P .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 237 (03) :752-757

[10]

A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity [J].

Goldoni, S. ;

Iozzo, R. A. ;

Kay, P. ;

Campbell, S. ;

McQuillan, A. ;

Agnew, C. ;

Zhu, J-X ;

Keene, D. R. ;

Reed, C. C. ;

Iozzo, R. V. .

ONCOGENE, 2007, 26 (03) :368-381

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