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J Biol Chem, Vol. 274, Issue 50, 35630-35638, December 10, 1999
From the Department of § Cell Biology and
Although much has been learned
regarding the importance of p38 mitogen-activated protein kinase in
inflammatory and stress responses, relatively little is known
concerning its role in differentiation processes. Recently, we
demonstrated that p38 mitogen-activated protein kinase activity is
necessary for the differentiation of 3T3-L1 fibroblasts into adipocytes
(Engelman, J. A., Lisanti, M. P., and Scherer, P. E. (1998) J. Biol. Chem. 273, 32111-32120). p38 activity
is high during the initial stages of differentiation but decreases
drastically as the fibroblasts undergo terminal differentiation into
adipocytes. However, it remains unknown whether activation of p38 is
sufficient to stimulate adipogenesis and whether the down-regulation of
p38 activity in mature adipocytes is critical for maintaining adipocyte
homeostasis. In this report, we have directly addressed these questions
by analyzing 3T3-L1 cell lines harboring a specific upstream activator
of p38 (a constitutively active mitogen-activated protein kinase kinase
6 (MKK6) mutant, MKK6(Glu)) under the control of an inducible promoter.
Induction of MKK6(Glu) in 3T3-L1 fibroblasts spurs adipocyte conversion in the absence of the hormonal mixture normally required for efficient differentiation of wild-type cells. However, activation of p38 in
adipocytes leads to cell death. Furthermore, treatment of 3T3-L1 fibroblasts with salicylate, a potent stimulator of p38, produces adipocyte-specific changes consistent with those observed with induction of MKK6(Glu). Expression of MKK6(Glu) in NIH-3T3 fibroblasts (cells that do not differentiate into adipocytes under normal conditions) is capable of converting these fibroblasts into lipid-laden fat cells following hormonal stimulation. Thus, p38 activation has
pro-adipogenic effects in multiple fibroblast cell lines.
Constitutively Active Mitogen-activated Protein Kinase Kinase 6 (MKK6) or Salicylate Induces Spontaneous 3T3-L1 Adipogenesis*
,, and
Molecular Pharmacology, Albert Einstein College of
Medicine, Bronx, New York 10461 and the ¶ Department of Pathology,
University of Alabama at Birmingham, Birmingham, Alabama 35294
*
This work was supported by National Institutes of Health
Medical Scientist Training Grant T32-GM07288 (to J. A. E.),
the Training Program in Cellular and Molecular Biology and Genetics
Grant T32-GM07491 (to A. H. B.), grants from the American
Diabetes Association (to P. E. S.), a pilot grant from the
Albert Einstein College of Medicine Diabetes Research and Training
Center (to P. E. S.), a grant from the Howard Hughes Research
Resources Program for Medical Schools (to P. E. S.), grants
from the G. Harold and Leila Y. Mathers Foundation (to M. P. L. and P. E. S.), National Institutes of Health NCI Grant
R01-CA-80250 (to M. P. L.), and grants from the Charles E. Culpeper Foundation (to M. P. L.) and the Sidney Kimmel Foundation for Cancer Research (to M. P. L.).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: Dept. of Cell
Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: 718-430-2928; Fax: 718-430-8574; E-mail: scherer@aecom.yu.edu.
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