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J. Biol. Chem., Vol. 275, Issue 45, 35617-35623, November 10, 2000
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From the Department of Pharmacology, Pennsylvania State University,
College of Medicine, Hershey, Pennsylvania 17033
We have previously shown that interleukin 1 (IL-1)-receptor-generated ceramide induces growth arrest in smooth
muscle pericytes by activating an upstream kinase in the
stress-activated protein kinase (SAPK) cascade. We now report the
mechanism by which ceramide activates the SAPK signaling pathway in
human embryonic kidney cells (HEK-293). We demonstrate that ceramide
activation of protein kinase C
Ceramide Directly Activates Protein Kinase C
to Regulate
a Stress-activated Protein Kinase Signaling Complex*
(PKC) mediates SAPK signal
complex formation and subsequent growth suppression. Ceramide directly
activates both immunoprecipitated and recombinant human PKC in
vitro. Additionally, ceramide activates SAPK activity, which is
blocked with a dominant-negative mutant of PKC.
Co-immunoprecipitation studies reveal that ceramide induces the
association of SAPK with PKC, but not with PKC
. In addition, ceramide treatment induces PKC association with phosphorylated SEK
and MEKK1, elements of the SAPK signaling complex. The biological role
of ceramide to induce cell cycle arrest is mimicked by overexpression of a constitutively active PKC. Together, these studies demonstrate that ceramide induces cell cycle arrest by enhancing the ability of
PKC to form a signaling complex with MEKK1, SEK, and
SAPK.
*
This work was supported by National Institutes of Health
Grant DK53715.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Pennsylvania State
University, The Milton S. Hershey Medical Center, Department of
Pharmacology, P. O. Box 850, Hershey, PA 17033. Tel.: 717-531-8964; Fax: 717-531-5013; E-mail: mxk38@email.psu.edu.
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