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J Biol Chem, Vol. 274, Issue 50, 35505-35513, December 10, 1999
From the Gastroenterology Section, Department of Medicine, The
University of Chicago, Chicago, Illinois 60637
1,25-Dihydroxyvitamin D3
(1,25(OH)2D3) is a potential chemopreventive
agent for human colon cancer. We have reported that 1,25(OH)2D3 specifically activated protein
kinase C-
1,25-Dihydroxyvitamin D3 Stimulates Activator
Protein-1-dependent Caco-2 Cell Differentiation*
(PKC-) and also caused a reduction in proliferation
while increasing apoptosis and differentiation in CaCo-2 cells, a cell
line derived from a human colon cancer. The mechanisms by which this
secosteroid influences these important cellular processes, however,
remain unclear. The transcription factor, activator protein-1 (AP-1), regulates many genes involved in these processes. Therefore, we asked
whether 1,25(OH)2D3 activated AP-1 in CaCo-2
cells and, if so, by what mechanisms?
1,25(OH)2D3 caused a time-dependent increase in AP-1 DNA binding activity and significantly enhanced the
protein and mRNA abundance of c-Jun, a component of AP-1. 1,25(OH)2D3 also induced a rapid and transient
activation of ERK2 (where ERK is extracellular signal-regulated kinase)
and a more persistent activation of JNK1 (where JNK Jun N-terminal
kinase). Transfection experiments revealed that
1,25(OH)2D3 also increased AP-1
gene-transactivating activity. This AP-1 activation was completely blocked by PD 098059, a specific mitogen-activated protein kinase/ERK kinase inhibitor, as well as by a dominant negative JNK or a dominant negative Jun, indicating that the AP-1 activation induced by
1,25(OH)2D3 was mediated by ERK and JNK. Using
a specific inhibitor of the Ca2+-dependent PKC
isoforms, Gö6976, and CaCo-2 cells stably transfected with
antisense PKC- cDNA, demonstrated that PKC- mediated the AP-1
activation induced by this secosteroid. Inhibition of JNK activation or
c-Jun protein expression significantly reduced
1,25(OH)2D3-induced alkaline phosphatase
activity, a marker of CaCo-2 cell differentiation, in
secosteroid-treated cells. Taken together, the present study demonstrated that 1,25(OH)2D3 stimulated AP-1
activation in CaCo-2 cells by a PKC-- and JNK-dependent
mechanism leading to increases in cellular differentiation.
*
This work was supported by National Institutes of Health
Grants DK39573, CA 36745 (to T. A. B and M. B.), and D30DK42086 (to T. A. B., Digestive Disease Research Core Center).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: Gastroenterology
Section, Dept. of Medicine, The University of Chicago, MC4076, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-9898; Fax:
773-702-2182; E-mail: tbrasitu@medicine.bsd.uchicago.edu.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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