Volume 272, Number 40, Issue of October 3, 1997 pp. 25062-25070
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Oncogenic Raf-1 Induces the Expression of Non-histone Chromosomal Architectural Protein HMGI-C via a p44/p42 Mitogen-activated Protein Kinase-dependent Pathway in Salivary Epithelial Cells

(Received for publication, March 17, 1997, and in revised form, June 13, 1997)

Danxi Li , H. Helen Lin , Martin McMahon ^§ , Huiyan Ma and David K. Ann

From the  Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, California 90033 and the ^§ DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304

The enzyme activity of mitogen-activated protein kinase (MAP kinase) increases in response to agents acting on a variety of cell surface receptors, including receptors linked to heterotrimeric G proteins. In this report, we demonstrated that Raf-1 protein kinase activity in the mouse parotid glands was induced by chronic isoproterenol administration in whole animals. To investigate the molecular nature underlying cellular responses to Raf-1 activation, we have stably transfected rat salivary epithelial Pa-4 cells with human Raf-1-estrogen receptor fusion gene (Raf-1:ER) and used mRNA differential display in search of messages induced by Raf-1:ER activation. Through this approach, the gene encoding non-histone chromosomal protein HMGI-C was identified as one of the target genes activated by oncogenic Raf-1 kinase. Activation of Raf-1 kinase resulted in a delayed and sustained increase of HMGI-C expression in the Pa-4 cells. The induction of HMGI-C mRNA level is sensitive to both the protein synthesis inhibitor cycloheximide and transcription inhibitor actinomycin D. The role of the extracellular signal-related kinase (ERK) signaling pathway in the HMGI-C induction was highlighted by the result that the MAP kinase kinase (MEK) inhibitor, PD 98059, blocked Raf-1:ER- and 12-O-tetradecanoylphorbol-13-acetate-stimulated HMGI-C induction. Altogether, these findings support the notion that the Raf/MEK/ERK signaling module, at least in part, regulates transcriptional activation of the chromosomal architectural protein HMGI-C.

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