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-induced apoptosis in polyamine depleted IEC-6 cells is mediated through the activation of ERK1/2
1 Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
* To whom correspondence should be addressed. E-mail: rray{at}physio1.utmem.edu.
Polyamines have been documented to play a critical role in the regulation of apoptosis in intestinal epithelial cells. We have recently reported that protection from
TNF-
/CHX-induced apoptosis in epithelial cells depleted of polyamines is mediated through the inactivation of a pro-apoptotic mediator, c-Jun N-terminal kinase. In this study we have addressed the involvement of
the MEK/ERK pathway in the regulation of apoptosis following polyamine depletion of IEC-6 cells. Polyamine depletion by -difluromethylornithine (DFMO) resulted in the sustained activation of ERK in response to TNF-/CHX treatment. Pretreatment of polyamine depleted IEC-6 cells with a cell membrane permeable MEK1/2 inhibitor, U0126, significantly inhibited TNF-/CHX-induced ERK phosphorylation and significantly increased DNA fragmentation, JNK activity and caspase-3 activity in response to TNF-/CHX. Moreover, the dose-dependency
of U0126-mediated inhibition of TNF-/CHX-induced ERK-phosphorylation correlated with the reversal of the anti-apoptotic effect of DFMO. IEC-6 cells expressing constitutively active MEK1 had decreased TNF-/CHX-induced JNK phosphorylation and were significantly
protected from apoptosis. Conversely, a dominant negative MEK1 resulted in high basal activation of JNK, cytochrome c release and spontaneous apoptosis. Polyamine depletion of the dominant negative MEK1 cells did not prevent JNK activation or cytochrome c release and failed to confer protection from both TNF-/CHX and camptothecin-induced apoptosis. Finally, expression of a dominant negative mutant of JNK significantly protected IEC-6 cells from TNF-/CHX-induced apoptosis. These data indicate that polyamine depletion results in the activation
of ERK, which inhibits JNK activation and protects cells from apoptosis.
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