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J. Biol. Chem., Vol. 280, Issue 27, 25388-25395, July 8, 2005
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From the Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612
Recent evidence has implicated the protein phosphatase PP5 in a variety of
signaling pathways. Whereas several proteins have been identified that
interact with PP5 and regulate its activity, a possibility of its regulation
by second messengers remains speculative. Activation of PP5 in vitro
by polyunsaturated fatty acids (e.g. arachidonic acid) and fatty
acyl-CoA esters (e.g. arachidonoyl-CoA) has been reported. We report
here that PP5 is strongly inhibited by micromolar concentrations of a natural
polyamine spermine. This inhibition was observed both in assays with a low
molecular weight substrate p-nitrophenyl phosphate as well as
phosphocasein and apoptosis signal-regulating kinase 1 (ASK1), thought to be a
physiological substrate of PP5. Furthermore, a decrease in polyamine levels in
COS-7 cells induced by 
-difluoromethylornithine (DFMO), an inhibitor of
ornithine decarboxylase, led to accelerated dephosphorylation of oxidative
stress-activated ASK1. This effect was suppressed by okadaic acid and by
siRNA-mediated PP5 depletion, indicating that the effect of polyamine levels
on ASK1 dephosphorylation was mediated by PP5. In line with the decreased ASK1
activation, polyamine depletion in COS-7 cells abrogated oxidative
stress-induced activation of caspase-3, which executes ASK1-induced apoptosis,
as well as caspase-3 activation induced by ASK1 overexpression, but had no
effect on basal caspase-3 activity. These results implicate polyamines,
emerging intracellular signaling molecules, as potential physiological
regulators of PP5. Our findings also suggest a novel mechanism of the
anti-apoptotic action of a decrease in polyamine levels via de-inhibition of
PP5 and accelerated dephosphorylation and deactivation of ASK1.
Received for publication, November 23, 2004 , and in revised form, May 5, 2005.
* This work was supported by National Institutes of Health Grants GM56159, GM65160, and HL06078 and by a grant from the American Heart Association (to T. A. V.-Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
An Established Investigator of the American Heart Association. To whom
correspondence should be addressed: Dept. of Pharmacology (MC 868), University
of Illinois, 835 S. Wolcott Ave., Chicago, IL 60612. Tel.: 312-996-9823; Fax:
312-996-1225; E-mail:
tvy{at}uic.edu.
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