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Vol. 11, Issue 9, 2915-2932, September 2000
*Departments of Radiation Oncology,
In primary hepatocytes and HepG2
hepatoma cells, prolonged activation of the p42/44 mitogen-activated
protein kinase (MAPK) pathway is associated with a reduction in DNA
synthesis, mediated by increased expression of the cyclin-dependent
kinase inhibitor protein p21 Cip-1/WAF1/mda6 (p21). This
study was performed to evaluate the contribution of transcriptional and
post-transcriptional regulation in this response. Prolonged activation
of the MAPK pathway in wild-type or p21 null hepatocytes caused a large
decrease and increase, respectively, in DNA synthesis. Prolonged
activation of the MAPK pathway in either wild-type or p21 antisense
HepG2 cells also caused large decreases and increases, respectively, in
DNA synthesis. MAPK signaling increased the phosphorylation of the
transcription factors Ets2, C/EBPMicrobiology and Immunology, and
#Pharmacology and Toxicology, Medical College of Virginia,
Virginia Commonwealth University, Richmond, Virginia 23298;
¶Department of Urology and Pathology, Columbia University
College of Physicians and Surgeons, New York, New York 10032;
§Department of Pathology, Baylor College of Medicine,
Houston, Texas 77071; Department of Molecular & Cell
Biology, University of California, Berkeley, California 94720; and
Department of Oncology and Hematology, University of
California, San Francisco, California 94143
, and C/EBP
, and rapidly
increased transcription from the p21 promoter via multiple Ets- and
C/EBP-elements within the enhancer region. Eight hours after MAPK
activation, loss of C/EBP or Ets2 function significantly reduced
MAPK-stimulated transcription from the p21 promoter and abolished
increased p21 protein expression. At this time, MAPK signaling
increased both p21 mRNA and p21 protein stabilities that were also
demonstrated to be essential for a profound increase in p21 protein
levels. Thirty-six hours after MAPK activation, transcription from the p21 promoter was still significantly reduced in cells without either
C/EBP or Ets2 function; however, these cells were now capable of
exhibiting a partial increase in p21 protein expression. In contrast,
loss of C/EBP function modestly reduced MAPK-stimulated transcription from the p21 promoter but strongly inhibited the ability
of prolonged MAPK activation to increase protein levels of p21. This
data suggested that prolonged enhancement of p21 protein levels may be
under posttranscriptional control. In agreement with this hypothesis,
prolonged MAPK signaling further increased p21 mRNA stability at
36 h, compared with the 8-h time point. Our data argue that MAPK
signaling increased p21 promoter activity via multiple
transcription factors, which alone were insufficient for a robust
prolonged increase in p21 protein levels in primary hepatocytes, and
that to increase p21 protein levels also required enhanced
stabilization of p21 mRNA and p21 protein. Collectively, these data
suggest that loss of transcription factor and mRNA/protein stabilization functions correlates with an inability of MAPK signaling to cause growth arrest versus proliferation in primary hepatocytes.
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