title: Differentiation state-selective roles of p38 isoforms in human intestinal epithelial cell anoikis.
abstract: OBJECTIVE
  Little is known of the signaling events implicated in the induction of human enterocytic anoikis. In the present study, we analyzed the role of the stress-activated protein kinase p38 in this process.
  
  
  METHODS
  Anoikis was induced in undifferentiated and differentiated enterocytes by inhibition of focal adhesion kinase (Fak; pharmacologic inhibition or overexpression of a dominant negative form) or beta1 integrins (antibody blocking), or by maintaining cells in suspension. Expression/activation parameters of p38 (isoforms alpha, beta, gamma, delta) and of the Fak/phosphatidylinositol-3-kinase (PI3-K)/Akt anoikis-suppressing pathways were analyzed. Kinase activities of p38 isoforms also were blocked by pharmacologic inhibitors or by overexpression of dominant-negative forms.
  
  
  RESULTS
  (1) p38 activation is sustained transiently after induction of anoikis in both undifferentiated and differentiated enterocytes; (2) such sustenance of p38 activation is associated with a down-regulation of the Fak/PI3-K/Akt pathway; (3) distinct profiles of p38 isoform expression are exhibited by undifferentiated (alpha, beta, gamma) and differentiated (alpha, gamma, delta) enterocytes; (4) none of the 4 known p38 isoforms was found to promote cell survival in either differentiation state; and (5) only p38beta and p38delta are required specifically for anoikis in undifferentiated and differentiated cells, respectively.
  
  
  CONCLUSIONS
  Distinct p38 isoforms play a major role in the induction of enterocytic anoikis and the regulation of such selective p38 isoform-mediated anoikis is linked with the state of cell differentiation. These data provide novel insights into the synchronized regulation of cell survival/death required in the epithelial renewal process along the human intestinal crypt-villus axis.
authors.affiliation: Canadian Institutes of Health Research Group on the Functional Development and Physiopathology of the Digestive Tract, Québec, Canada. Pierre.H.Vachon@Usherbrooke.ca
authors.forename: Pierre H
authors.initials: PH
authors.lastname: Vachon
authors.forename: Charlène
authors.initials: C
authors.lastname: Harnois
authors.forename: Amélie
authors.initials: A
authors.lastname: Grenier
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dufour
authors.forename: Véronique
authors.initials: V
authors.lastname: Bouchard
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Jacques
authors.initials: J
authors.lastname: Landry
authors.forename: Jean-Fraçois
authors.initials: JF
authors.lastname: Beaulieu
authors.forename: Anne
authors.initials: A
authors.lastname: Vézina
authors.forename: Anders Bondo
authors.initials: AB
authors.lastname: Dydensborg
authors.forename: Rémy
authors.initials: R
authors.lastname: Gauthier
authors.forename: André
authors.initials: A
authors.lastname: Côté
authors.forename: Jean-Fraçois
authors.initials: JF
authors.lastname: Drolet
authors.forename: Fraçois
authors.initials: F
authors.lastname: Lareau
mesh_terms: D023102:Anoikis / Q000502:physiology*; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology; D020895:Enterocytes / Q000166:cytology / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000201:enzymology*; D007527:Isoenzymes / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C496050:PTK2 protein, human; C494918:AKT1 protein, human