QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stappenbeck, T. S. Articles by Gordon, J. I. Search for Related Content PubMed PubMed Citation Articles by Stappenbeck, T. S. Articles by Gordon, J. I.

Extranuclear sequestration of phospho-Jun N-terminal kinase and distorted villi produced by activated Rac1 in the intestinal epithelium of chimeric mice

¹ Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA
² Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA

*Author for correspondence (e-mail: jgordon{at}molecool.wustl.edu)

Accepted April 17, 2001

Previously, we used a genetic mosaic system to conduct an in vivo analysis of the effects of Rac1 activation on the developing intestinal epithelium (

Stappenbeck, T. S. and Gordon, J. I. (2000) Development 127, 2629-2642

). Expression of a constitutively active human Rac1 (Rac1Leu61) in the 129/Sv-derived small intestinal epithelium of C57Bl/6-ROSA26129/Sv chimeric mice led to precocious differentiation of some lineages with accompanying alterations in their apical actin. We have now explored the underlying mechanisms. Rac1Leu61 leads to accumulation of the 46 kDa form of phosphorylated Jun N-terminal kinase (p-Jnk) in the apical cytoplasm, but not in the nucleus of E18.5 proliferating and differentiating intestinal epithelial cells. The effect is cell-autonomous, selective for this mitogen-activated protein kinase family member, and accompanied by apical cytoplasmic accumulation of p21-activated kinase. c-Jun, a downstream nuclear target of p-Jnk, does not show evidence of enhanced phosphorylation, providing functional evidence for cytoplasmic sequestration of p-Jnk in Rac1Leu61-expressing epithelium. In adult chimeras, Rac1 activation augments cell proliferation in crypts of Lieberkühn, without a compensatory change in basal apoptosis and produces a dramatic, very unusual widening of villi. These results reveal a novel in vivo paradigm for Rac1 activation involving p-Jnk-mediated signaling at a distinctive extra-nuclear site, with associated alterations in the actin cytoskeleton. They also provide a new perspective about the determinants of small intestinal villus morphogenesis.

Key words: Rac, MAP kinases, Actin, Mouse, Intestine, Epithelium

This article has been cited by other articles:

				A. Malliri, T. P. Rygiel, R. A. van der Kammen, J.-Y. Song, R. Engers, A. F. L. Hurlstone, H. Clevers, and J. G. Collard The Rac Activator Tiam1 Is a Wnt-responsive Gene That Modifies Intestinal Tumor Development J. Biol. Chem., January 6, 2006; 281(1): 543 - 548. [Abstract] [Full Text] [PDF]

				Y. Wang, H. Iordanov, E. A. Swietlicki, L. Wang, C. Fritsch, T. Coleman, C. F. Semenkovich, M. S. Levin, and D. C. Rubin Targeted Intestinal Overexpression of the Immediate Early Gene tis7 in Transgenic Mice Increases Triglyceride Absorption and Adiposity J. Biol. Chem., October 14, 2005; 280(41): 34764 - 34775. [Abstract] [Full Text] [PDF]

				C. Huang, K. Jacobson, and M. D. Schaller MAP kinases and cell migration J. Cell Sci., September 15, 2004; 117(20): 4619 - 4628. [Abstract] [Full Text] [PDF]

				P. Mehlen and E. R. Fearon Role of the Dependence Receptor DCC in Colorectal Cancer Pathogenesis J. Clin. Oncol., August 15, 2004; 22(16): 3420 - 3428. [Abstract] [Full Text] [PDF]

				T. S. Stappenbeck, J. C. Mills, and J. I. Gordon Molecular features of adult mouse small intestinal epithelial progenitors PNAS, February 4, 2003; 100(3): 1004 - 1009. [Abstract] [Full Text] [PDF]