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.
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 (DeltaRaf-1:ER) and used mRNA differential display in search of messages induced by DeltaRaf-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 DeltaRaf-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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Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, California 90033, USA.
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McMahon
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D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002875:Chromosomes / Q000502:physiology*; D017931:DNA Primers; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D025743:HMGA2 Protein; D006609:High Mobility Group Proteins / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010306:Parotid Gland / Q000166:cytology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic
D017931:DNA Primers; D025743:HMGA2 Protein; D006609:High Mobility Group Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D007545:Isoproterenol