title: Differential sensitivity to apoptosis between the human small and large intestinal mucosae: linkage with segment-specific regulation of BCL-2 homologs and involvement of signaling pathways.
abstract: The small and large intestines differ in their expression profiles of Bcl-2 homologs. Intestinal segment-specific Bcl-2 homolog expression profiles are acquired as early as by mid-gestation (18-20 weeks) in man. In the present study, we examined the question whether such distinctions underlie segment-specific control mechanisms of intestinal cell survival. Using mid-gestation human jejunum and colon organotypic cultures, we analyzed the impact of growth factors (namely insulin; 10 microg/ml) and pharmacological compounds that inhibit signal transduction molecules/pathways (namely tyrosine kinases, Fak, P13-K/Akt, and MEK/Erk) on cell survival and Bcl-2 homolog expression (anti-apoptotic: Bcl-2, Bcl-X(L), Mcl-1; pro-apoptotic: Bax, Bak, Bad). The relative activation levels of p125Fak, p42Erk-2, and p57Akt were analyzed as well. Herein, we report that (1) the inhibition of signal transduction molecules/pathways revealed striking differences in their impact on cell survival in the jejunum and colon (e.g., the inhibition of p125Fak induced apoptosis with a significantly greater extent in the jejunum [approximately 43%] than in the colon [approximately 24%]); (2) sharp distinctions between the two segments were noted in the modulatory effects of the various treatments on Bcl-2 homolog steady-state levels (e.g., inhibition of tyrosine kinase activities in the jejunum down-regulated all anti-apoptotics analyzed while increasing Bax, whereas the same treatment in the colon down-regulated Bcl-X(L) only and increased all pro-apoptotics); and (3) in addition to their differential impact on cell survival and Bcl-2 homolog expression, the MEK/Erk and P13-K/Akt pathways were found to be distinctively regulated in the jejunum and colon mucosae (e.g., insulin in the jejunum increased p42Erk-2 activation without affecting that of p57Akt, whereas the same treatment in the colon decreased p42Erk-2 activation while increasing that of p57Akt). Altogether, these data show that intestinal cell survival is characterized by segment-specific susceptibilities to apoptosis, which are in turn linked with segmental distinctions in the involvement of signaling pathways and the regulation of Bcl-2 homolog steady-state levels. Therefore, these indicate that cell survival is subject to segment-specific control mechanisms along the proximal-distal axis of the intestine.
authors.affiliation: Département d'anatomie et de biologie cellulaire, Faculté de médecine, Université de Sherbrooke, QC, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Gauthier
authors.forename: P
authors.initials: P
authors.lastname: Laprise
authors.forename: E
authors.initials: E
authors.lastname: Cardin
authors.forename: C
authors.initials: C
authors.lastname: Harnois
authors.forename: A
authors.initials: A
authors.lastname: Plourde
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.forename: A
authors.initials: A
authors.lastname: Vézina
authors.forename: P H
authors.initials: PH
authors.lastname: Vachon
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival; D003106:Colon / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005326:Fetal Proteins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018507:Gene Expression Regulation, Developmental; D019254:Genes, bcl-2; D005865:Gestational Age; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D007583:Jejunum / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: D002352:Carrier Proteins; D005326:Fetal Proteins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007328:Insulin; D048728:MAP Kinase Kinase Kinase 1; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C494819:BAD protein, human; C494772:BAK1 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C496050:PTK2 protein, human; C494918:AKT1 protein, human; C482576:MAP3K1 protein, human