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

The small and large intestines differ in their expression profiles of Bcl-2 homologs. Intestinal segment-specific Bcl-2 homolog expression profiles ar e acquired as early as by mid-gestation (18-20 weeks) in man. In the presen t study, we examined the question whether such distinctions underlie segmen t-specific control mechanisms of intestinal cell survival. Using mid-gestat ion human jejunum and colon organotypic cultures, we analyzed the impact of growth factors (namely insulin; 10 mug/ml) and pharmacological compounds t hat inhibit signal transduction molecules/ pathways (namely tyrosine kinase s, Fak, PI3-K/Akt, and MEK/Erk) on cell survival and Bcl-2 homolog expressi on (antiapoptotic: Bcl-2, Bcl-X-L, Mcl-1; pro-apoptotic: Bax, Bak, Bad). Th e relative activation levels of p125(Fak), p42(Erk-2),and p57(Akt) were ana lyzed as well. Herein, we report that (1) the inhibition of signal transduc tion molecules/pathways revealed striking differences in their impact on ce ll survival in the jejunum and colon (e.g., the inhibition of p125(Fak) ind uced apoptosis with a significantly greater extent in the jejunum [similar to 43%] than in the colon [similar to 24%]); (2) sharp distinctions between the two segments were noted in the modulatory effects of the various treat ments on Bcl-2 homolog steady-state levels (e.g., inhibition of tyrosine ki nase activities in the jejunum down-regulated all anti-apoptotics analyzed while increasing Bax, whereas the same treatment in the colon down-regulate d Bcl-X-L only and increased all pro-apoptotics); and (3) in addition to th eir differential impact on cell survival and Bcl-2 homolog expression, the MEK/ Erk and Pl3-K/Akt pathways were found to be distinctively regulated in the jejunum and colon mucosae (e.g., insulin in the jejunum increased p42( Erk-2) activation without affecting that of p57(Akt), whereas the same trea tment in the colon decreased p42(Erk-2) activation while increasing that of p57Akt). Altogether, these data show that intestinal cell survival is char acterized by segment-specific susceptibilities to apoptosis, which are in t urn linked with segmental distinctions in the involvement of signaling path ways and the regulation of Bcl-2 homolog steady-state levels. Therefore, th ese indicate that cell survival is subject to segment-specific control mech anisms along the proximal-distal axis of the intestine. J. Cell. Biochem. 8 2: 339-355, 2001. (C) 2001 Wiley-Liss, Inc.