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J Biol Chem, Vol. 274, Issue 50, 35505-35513, December 10, 1999

1,25-Dihydroxyvitamin D₃ Stimulates Activator Protein-1-dependent Caco-2 Cell Differentiation^*

Anping Chen, Bernard H. Davis, Marc Bissonnette, Beth Scaglione-Sewell, and Thomas A. Brasitus

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- (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.

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^* 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.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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