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Title: SHIGA-LIKE TOXIN INDUCES DECREASED EXPRESSION OF THE ANTI-APOPTOTIC PROTEIN MEL-1 CONCOMITANT WITH THE ONSET OF ENDOTHELIAL APOPTOSIS

Author
item ERWERT, RYAN - U WASHINGTON SEATTLE
item TUPPER, JOAN - U WASHINGTON SEATTLE
item WINN, ROBERT - U WASHINGTON SEATTLE
item HARLAN, JOHN - U WASHINGTON SEATTLE
item Bannerman, Douglas

Submitted to: Microbial Pathogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/2/2003
Publication Date: 8/1/2003
Citation: ERWERT, R.D., TUPPER, J.C., WINN, R.R., HARLAN, J.M., BANNERMAN, D.D. SHIGA-LIKE TOXIN INDUCES DECREASED EXPRESSION OF THE ANTI-APOPTOTIC PROTEIN MEL-1 CONCOMITANT WITH THE ONSET OF ENDOTHELIAL APOPTOSIS. MICROBIAL PATHOGENESIS. 2003. Vol. 35, pp. 87-93.

Interpretive Summary: Shiga-like toxin(SLT)-producing strains of Escherichia coli (STEC) have been implicated in naturally occurring outbreaks of hemorrhagic colitis in calves, edema diseases in pigs, as well as food-borne outbreaks of gastroenteritis in humans. The intestinal tracts of a variety of domesticated animals, including cows, pigs, chicken and sheep, serve as a reservoir for STEC. In addition, both STEC and SLT have been detected in milk obtained from bovine mammary glands. Consumption of STEC-contaminated food products can result in diarrhea and the development ofhemorrhagic colitis and hemolytic uremic syndrome, the latter of which is a leading cause of acute renal failure in children. It is well established that the ascular endothelium is a key host target of SLT and that SLT is directly responsible for much of the endothelial cell injury associated with STEC infection. The presentmanuscript demonstrates that SLT inhibits the expression of the cytoprotective protein, Mcl-1, thus, shedding light on a possible mechanism by which SLT induces host cell injury. Understanding the mechanism by which SLT-induces injury maylead to the development of therapeutic interventions that can block these deleterious effects and confer protection to the host organism.

Technical Abstract: Shiga-like toxin (SLT)-1 has been implicated in the pathogenesis of several human and animal disease states. A key target of SLT-1 is the endothelial cell. It has previously been established that SLT-1 induces endothelial apoptosis, although the mechanism by which this occurs remains unknown. In the present report, we demonstrate that SLT-1 inhibits the expression of the anti-apoptotic Bcl-2 family member, Mcl-1. Decreased expression of Mcl-1 precedes the onset of SLT-1 induced apoptosis. Further, SLT-1-mediated decrements in Mcl-1 expression correlate in a dose-dependent manner with sensitization to SLT-induced apoptosis. Finally, inhibition of Mcl-1 degradation with the proteasome inhibitor, lactacystin, inhibits SLT-1-induced apoptosis. Together, these data suggest a role for Mcl-1 in protecting endothelial cells against SLT-1-induced apoptosis.