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*

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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 μg/ml) and pharmacological compounds that inhibit signal transduction molecules/pathways (namely tyrosine kinases, Fak, PI3‐K/Akt, and MEK/Erk) on cell survival and Bcl‐2 homolog expression (anti‐apoptotic: Bcl‐2, Bcl‐XL, 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 [∼43%] than in the colon [∼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‐XL 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 PI3‐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. J. Cell. Biochem. 82: 339–355, 2001.
Funding Information
  • the Canadian Institutes of Health Research (CIHR) (MGC-15186)