ONCOGENIC RAF-1 INDUCES THE EXPRESSION OF NONHISTONE CHROMOSOMAL ARCHITECTURAL PROTEIN HMGI-C VIA A P44 P42 MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT PATHWAY IN SALIVARY EPITHELIAL-CELLS/

The enzyme activity of mitogen-activated protein kinase (MAP kinase) i ncreases in response to agents acting on a variety of cell surface rec eptors, including receptors linked to heterotrimeric G proteins, In th is report, we demonstrated that Raf-1 protein kinase activity in the m ouse parotid glands was induced by chronic isoproterenol administratio n in whole animals, To investigate the molecular nature underlying cel lular responses to Raf-1 activation, we have stably transfected rat sa livary epithelial Pa-4 cells with human Raf-1-estrogen receptor fusion gene (Delta Raf-1:ER) and used mRNA differential display in search of messages induced by Delta Raf-1:ER activation, Through this approach, the gene encoding non-histone chromosomal protein HMGI-C was identifi ed as one of the target genes activated by oncogenic Raf-1 kinase, Act ivation of Raf-1 kinase resulted in a delayed and sustained increase o f HMGI-C expression in the Pa-4 cells, The induction of HMGI-C mRNA le vel is sensitive to both the protein synthesis inhibitor cycloheximide and transcription inhibitor actinomycin D, The role of the extracellu lar signal-related kinase (ERK) signaling pathway in the HMGI-C induct ion was highlighted by the result that the MAP kinase kinase (MEK) inh ibitor, PD 98059, blocked Delta Raf-1:ER-and 12-O-tetradecanoylphorbol -13-acetate-stimulated HMGI-C induction, Altogether, these findings su pport the notion that the Raf/MEK/ERK signaling module, at least in pa rt, regulates transcriptional activation of the chromosomal architectu ral protein HMGI-C.