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J Biol Chem, Vol. 273, Issue 33, 21137-21144, August 14, 1998
From the Division of Endocrinology and Metabolism, the Center for
Osteoporosis and Metabolic Bone Diseases, University of Arkansas
for Medical Sciences, and the McClellan Veterans Affairs Medical
Center, Geriatric Research, Education, and Clinical Center,
Little Rock, Arkansas 72205
The cyclin-dependent kinase
inhibitor p21WAF1,CIP1,SDI1 plays a critical role in cell
differentiation, and it has been shown to confer resistance to
apoptosis. Based on this, and on evidence that activation of the
gp130/signal transducer and activator of transcription (STAT) signal
transduction pathway by interleukin (IL)-6 type cytokines promotes
differentiation and prevents apoptosis in osteoblastic cells, we have
investigated the possibility that p21 is a downstream effector of this
signaling pathway in osteoblasts. We report that either oncostatin M
(OSM) or IL-6 plus soluble IL-6 receptor increased the levels of p21
mRNA and protein in the osteoblast-like human osteosarcoma cell
line MG63 and stimulated the activity of a 2.4-kilobase pair segment of
the human p21 gene promoter. Further, nuclear extracts from
cytokine-stimulated MG63 cells formed protein-DNA complexes with a
19-base pair nucleotide fragment of the p21 promoter containing a
single STAT response element. The identity of the binding proteins as
Stat3 and Stat1 was demonstrated with specific antibodies. In addition,
and in support of a mediating role of STATs in the activation of the
p21 promoter, overexpression of Stat3 potentiated the cytokine effect
on the p21 promoter; whereas a dominant negative Stat3, or a mutation
of the STAT response element on the promoter, significantly reduced the
cytokine effect. Finally, antisense oligonucleotides complementary to
p21 mRNA inhibited OSM-induced stimulation of alkaline phosphatase
expression and antagonized the protective effect of OSM on
anti-Fas-induced apoptosis. These results demonstrate that p21 is a
downstream effector of gp130/Stat3 activation and a critical mediator
of the pro-differentiating and anti-apoptotic effects of IL-6 type cytokines on human osteoblastic cells.
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