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Am J Physiol Cell Physiol 280: C1540-C1554, 2001;
0363-6143/01 $5.00
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Vol. 280, Issue 6, C1540-C1554, June 2001

Human intestinal epithelial cell survival: differentiation state-specific control mechanisms

Rémy Gauthier1, Charlène Harnois1, Jean-François Drolet1, John C. Reed2, Anne Vézina1, and Pierre H. Vachon1,3

1 Canadian Institutes of Health Research Group on the Functional Development and Physiopathology of the Digestive Tract, Département d'Anatomie et de Biologie Cellulaire, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4; 2 The Burnham Institute, La Jolla Cancer Research Center, La Jolla, California 92037; and 3 Thématique de Recherche en Physiopathololgie Digestive du Centre de Recherches Cliniques du CHUS, Fleurimont, Quebec, Canada J1H 5N4

To investigate whether human intestinal epithelial cell survival involves distinct control mechanisms depending on the state of differentiation, we analyzed the in vitro effects of insulin, pharmacological inhibitors of Fak, MEK/Erk, and PI3-K/Akt, and integrin (beta 1, beta 4)-blocking antibodies on the survival of the well-established human Caco-2 enterocyte-like and HIEC-6 cryptlike cell models. In addition, relative expression levels of six Bcl-2 homologs (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, and Bad) and activation levels of Fak, Erk-2, and Akt were analyzed. Herein, we report that 1) the enterocytic differentiation process results in the establishment of distinct profiles of Bcl-2 homolog expression levels, as well as p125Fak, p42Erk-2, and p57Akt activated levels; 2) the inhibition of Fak, of the MEK/Erk pathway, or of PI3-K, have distinct impacts on enterocytic cell survival in undifferentiated (subconfluent Caco-2, confluent HIEC-6) and differentiated (30 days postconfluent Caco-2) cells; 3) exposure to insulin and the inhibition of Fak, MEK, and PI3-K resulted in differentiation state-distinct modulations in the expression of each Bcl-2 homolog analyzed; and 4) Fak, beta 1 and beta 4 integrins, as well as the MEK/Erk and PI3-K/Akt pathways, are distinctively involved in cell survival depending on the state of cell differentiation. Taken together, these data indicate that human intestinal epithelial cell survival is regulated according to differentiation state-specific control mechanisms.

anoikis; apoptosis; gut; intestine; signal transduction


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