MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression.

Wang D, Yang W, Du J, Devalaraja MN, Liang P, Matsumoto K, Tsubakimoto K, Endo T, Richmond A
Oncogene. 2000 19 (40): 4647-59

PMID: 11030154 · PMCID: PMC2667445 · DOI:10.1038/sj.onc.1203820

The MGSA/GRO protein is endogenously expressed in almost 70% of the melanoma cell lines and tumors, but not in normal melanocytes. We have previously demonstrated that over-expression of human MGSA/GROalpha, beta or gamma in immortalized murine melanocytes (melan-a cells) enables these cells to form tumors in SCID and nude mice. To examine the possibility that the MGSA/GRO effect on melanocyte transformation requires expression of other genes, differential display was performed. One of the mRNA's identified in the screen as overexpressed in MGSA/GRO transformed melan-a clones was the newly described M-Ras or R-Ras3 gene, a member of the Ras gene superfamily. Over-expression of MGSA/GRO upregulates M-Ras expression at both the mRNA and protein levels, and this induction requires an intact glutamine-leucine-arginine (ELR)-motif in the MGSA/GRO protein. Western blot examination of Ras expression revealed that K- and N-Ras proteins are also elevated in MGSA/GRO-expressing melan-a clones, leading to an overall increase in the amount of activated Ras. MGSA/GRO-expressing melan-a clones exhibited enhanced AP-1 activity. The effects of MGSA/GRO on AP-1 activation could be mimicked by over-expression of wild-type M-Ras or a constitutively activated M-Ras mutant in control melan-a cells as monitored by an AP-1-luciferase reporter, while expression of a dominant negative M-Ras blocked AP-1-luciferase activity in MGSA/GRO-transformed melan-a clones. In the in vitro transformation assay, over-expression of M-Ras mimicked the effects of MGSA/GRO by inducing cellular transformation in control melan-a cells, while over-expression of dominant negative M-Ras in MGSA/GROalpha-expressing melan-a-6 cells blocked transformation. These data suggest that MGSA/GRO-mediated transformation requires Ras activation in melanocytes.

MeSH Terms (30)

Animals Autocrine Communication Cell Line, Transformed Cell Transformation, Neoplastic Chemokine CXCL1 Chemokines, CXC Chemotactic Factors Clone Cells Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, ras Genes, Reporter Growth Substances Humans Intercellular Signaling Peptides and Proteins MAP Kinase Signaling System Melanocytes Melanoma Mice Monomeric GTP-Binding Proteins Neoplasm Proteins Protein Isoforms Receptors, Cytokine Recombinant Fusion Proteins RNA, Messenger RNA, Neoplasm Signal Transduction Subtraction Technique Transcription Factor AP-1 Transfection

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