M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line.
M-Ras, a recently identified homologue of p21 Ras, is widely expressed, with levels of the 29-kD protein in spleen, thymus, and NIH 3T3 fibroblasts equaling or exceeding those of p21 Ras. A G22V mutant of M-Ras was constitutively active and its expression in an interleukin-3 (IL-3)-dependent mast cell/megakaryocyte cell line ... resulted in increased survival in the absence of IL-3, increased growth in IL-4, and, at high expression levels, in factor-independent growth. Expression of M-Ras G22V, however, had a negative effect on growth in the presence of IL-3, suggesting that M-Ras has both positive and negative effects on growth. Expression of M-Ras G22V in NIH-3T3 fibroblasts resulted in morphological transformation and growth to higher cell densities. M-Ras G22V induced activation of the c-fos promoter, and bound weakly to the Ras-binding domains of Raf-1 and RalGDS. Expression of a mutant of M-Ras G22V that was no longer membrane-bound partially inhibited (40%) activation of the c-fos promoter by N-Ras Q61K, suggesting that M-Ras shared some, but not all, of the effectors of N-Ras. An S27N mutant of M-Ras, like the analogous H-Ras S17N mutant, was a dominant inhibitor of activation of the c-fos promoter by constitutively active Src Y527F, suggesting that M-Ras and p21 Ras shared guanine nucleotide exchange factors and are likely to be activated in parallel. Moreover, M-Ras was recognized by the monoclonal anti-Ras antibody Y13-259, commonly used to study the function and activity of p21 Ras. Mammalian M-Ras and a Caenorhabditis elegans orthologue exhibit conserved structural features, and these are likely to mediate activation of distinctive signaling paths that function in parallel to those downstream of p21 Ras.
Mesh Terms:
3T3 Cells, Amino Acid Sequence, Amino Acid Substitution, Animals, Antibodies, Cell Division, Cell Line, Cell Line, Transformed, Culture Media, Conditioned, Epitopes, Humans, Interleukin-3, Mice, Molecular Sequence Data, Molecular Weight, Monomeric GTP-Binding Proteins, Mutagenesis, Site-Directed, Proto-Oncogene Proteins p21(ras), Recombinant Proteins, Sequence Alignment, Tumor Cells, Cultured
3T3 Cells, Amino Acid Sequence, Amino Acid Substitution, Animals, Antibodies, Cell Division, Cell Line, Cell Line, Transformed, Culture Media, Conditioned, Epitopes, Humans, Interleukin-3, Mice, Molecular Sequence Data, Molecular Weight, Monomeric GTP-Binding Proteins, Mutagenesis, Site-Directed, Proto-Oncogene Proteins p21(ras), Recombinant Proteins, Sequence Alignment, Tumor Cells, Cultured
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Date: Oct. 01, 1999
PubMed ID: 10498616
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