Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The human Ki-ras gene was previously reported to contain two alternative fourth exons which encode two distinct p21 proteins differing only at their carboxy termini. The present study shows that either p21 protein is able on its own to transform NIH 3T3 cells to a tumorigenic state.
Mol Cell Biol 1986 Apr
PMID:A human Ki-ras oncogene encodes two transforming p21 proteins. 353

An Ala-to-Thr substitution at position 59 activates the transforming properties of the p21ras protein without impairment of GTPase activity, a biochemical alteration associated with other activating mutations. To investigate the basis for the transforming properties of the Thr-59 mutant, we characterized guanine nucleotide release. This reaction exhibited a slow rate and stringent temperature requirements. To further dissect the release reaction, we used monoclonal antibodies directed against different epitopes of the p21 molecule. One monoclonal specifically interfered with nucleotide release, while others which recognized different regions of the molecule blocked nucleotide binding. Mutants with the Thr-59 substitution exhibited a three- to ninefold-higher rate of GDP and GTP release than normal p21 or mutants with other activating lesions. This alteration in the Thr-59 mutant would have the effect of increasing its rate of nucleotide exchange. In an intracellular environment with a high GTP/GDP ratio, this would favor the association of GTP with the Thr-59 mutant. Consistent with knowledge of known G-regulatory proteins, these findings support a model in which the p21-GTP complex is the biologically active form of the p21 protein.
Mol Cell Biol 1986 Dec
PMID:Activation of ras p21 transforming properties associated with an increase in the release rate of bound guanine nucleotide. 354 Jun 8

We characterized the normal (Gly-12) and two mutant (Asp-12 and Val-12) forms of human N-ras proteins produced by Escherichia coli. No significant differences were found between normal and mutant p21 proteins in their affinities for GTP or GDP. Examination of GTPase activities revealed significant differences between the mutant p21s: the Val-12 mutant retained 12% of wild-type GTPase activity, whereas the Asp-12 mutant retained 43%. Both mutant proteins, however, were equally potent in causing morphological transformation and increased cell motility after their microinjection into quiescent NIH 3T3 cells. This lack of correlation between transforming potency and GTPase activity or guanine nucleotide binding suggests that position 12 mutations affect other aspects of p21 function.
Mol Cell Biol 1987 Jan
PMID:Biochemical and biological properties of the human N-ras p21 protein. 355 Apr 23

Microinjection of transforming p21 ras protein induces maturation of Xenopus laevis oocytes, and the induction is blocked by coinjection of monoclonal antibody (Y13-259) against p21 ras proteins. Similar to other inducing agents, the effect of p21 ras protein is mediated via the appearance of maturation or meiosis-promoting factor activity. In addition, the neutralizing antibody markedly reduces oocyte maturation after insulin induction, whereas it fails to inhibit progesterone induction. Our results suggest that insulin induces maturation of oocytes via a different pathway than that of steroidal agents. The induction by insulin is ras dependent, and the action of ras may be directed at the steps before meiosis-promoting factor autocatalytic activation. These results suggest a role of p21 ras protein in the events associated with amphibian oocyte maturation.
Mol Cell Biol 1987 Mar
PMID:Insulin induction of Xenopus laevis oocyte maturation is inhibited by monoclonal antibody against p21 ras proteins. 355 Apr 36

The requirements for transformation of rat embryo fibroblasts (REFs) by transfected ras and myc oncogenes were explored. Under conditions of dense monolayer culture, neither oncogene was able to transform REFs on its own. However, the introduction of a ras oncogene together with a selectable neomycin resistance marker into REFs allowed killing of the normal nontransfected cells and the outgrowth of colonies of ras transformants, 10% of which survived crisis and became tumorigenic. These cells expressed greater than 10-fold-higher levels of ras p21 than tumorigenic cells cotransfected with ras and myc oncogenes. The myc oncogene similarly was unable to induce tumorigenic conversion of REFs unless especially refractile colonies of oncogene-bearing cells, produced by use of a cotransfected selectable marker, were picked and subcultured. Tumorigenic conversion of REFs by single transfected oncogenes appears to require special culture conditions and high levels of gene expression.
Mol Cell Biol 1986 Jun
PMID:Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts. 378 84

Morphologic transformation of NIH 3T3 mouse cells occurs upon transfection of these cells with large amounts (greater than or equal to 10 micrograms) of recombinant DNA molecules carrying the normal human H-ras-1 proto-oncogene. We provide experimental evidence indicating that transformation of these NIH 3T3 cells results from the combined effect of multiple copies of the H-ras-1 proto-oncogene rather than from spontaneous mutation of one of the transfected H-ras-1 clones (E. Santos, E.P. Reddy, S. Pulciani, R.J. Feldman, and M. Barbacid, Proc. Natl. Acad. Sci. USA 80:4679-4683, 1983). Levels of H-ras-1 RNA and p21 expression are highly elevated in the NIH 3T3 transformants, and in those cases examined, these levels correlate with the malignant properties of these cells. We have also investigated the presence of amplified ras genes in a variety of human carcinomas. In 75 tumor biopsies, we found amplification of the human K-ras-2 locus in one carcinoma of the lung. These results indicate that ras gene amplification is an alternative pathway by which ras genes may participate in the development of human neoplasia.
Mol Cell Biol 1985 Oct
PMID:ras gene Amplification and malignant transformation. 391 35

The high prevalence of ras oncogenes in human tumors has given increasing impetus to efforts aimed at elucidating the structure and function of their p21 products. To identify functionally important domains of the p21 protein, antibodies were generated against synthetic peptides corresponding to various regions of the protein. Antibodies directed against a synthetic peptide fragment corresponding to amino acid residues 161 to 176 in the carboxy-terminal region of the H-ras-encoded p21 molecule specifically recognized H-ras-encoded p21 proteins. This antibody was also shown to strikingly and specifically inhibit the guanine nucleotide-binding function of the p21 protein. The inability of p21 protein to bind guanine nucleotides was associated with a lack of autophosphorylation or GTPase activities. These studies suggest that a region toward its carboxy terminus is directly or indirectly involved in the guanine nucleotide-binding function of the p21 molecule.
Mol Cell Biol 1985 Nov
PMID:Antibody of predetermined specificity to a carboxy-terminal region of H-ras gene products inhibits their guanine nucleotide-binding function. 391 72

We expressed normal and activated human cellular Ha-ras cDNAs which encode 21,000-dalton polypeptides (p21s) in Saccharomyces cerevisiae by their insertion into a 2 micron-based replicating plasmid vector under 3-phosphoglycerate kinase promoter control. We found that newly synthesized p21 in S. cerevisiae was produced as a soluble precursor (pro-p21) which matured into a form electrophoretically indistinguishable from the processed form (p21) observed in mammalian cells. Coincident with the processing event was translocation to a membrane component, suggesting a coupling of the two events. Using vectors that direct the synthesis of p21 variants possessing the ability to autophosphorylate in vitro, we found that processing of p21 did not significantly affect this autophosphorylation reaction. In contrast to Escherichia coli, marked phenotypic changes were observed in S. cerevisiae as a consequence of the synthesis of p21, including reduction in growth rate and induction of flocculation. Accompanying these phenotypic alterations was a significant elevation of adenylate cyclase activity.
Mol Cell Biol 1985 Oct
PMID:Expression of normal and activated human Ha-ras cDNAs in Saccharomyces cerevisiae. 393 54

We isolated cDNA clones corresponding to the normal human Ki-ras2 gene and to the transforming allele of the Ki-ras2 gene present in the human colon carcinoma cell line SW480. These two cDNAs encode p21 proteins which differ only at the amino acid at position 12. The normal cDNA encodes a glycine at this position, and the transforming allele encodes a valine. Expression of these cDNAs indicates that this amino acid 12 alteration confers oncogenic activity on the mutated gene. Analysis of the relationship of the cDNAs and Kirsten sarcoma virus ras gene to a genomic clone allowed us to identify two alternative 3' coding exons for the Ki-ras2 gene, suggesting that the Ki-ras2 gene encodes two p21 proteins which differ at their carboxy termini. Our data also show that only one of the p21s is necessary to convert cells to a tumorigenic phenotype.
Mol Cell Biol 1984 Aug
PMID:Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-oncogene. 609 20

The EJ bladder carcinoma oncogene is activated by a point mutation in the c-rasH proto-oncogene at the 12th amino acid codon. In an attempt to understand the mechanism of oncogenic activation, a comparative study was undertaken to examine the metabolic turnover and subcellular localization of the p21 protein encoded by the EJ oncogene, the viral oncogene, and its normal cellular homolog. Pulse-labeling experiments indicated that both c-ras p21 proteins were synthesized by a very similar pathway, as was observed for the viral p21 protein of Harvey murine sarcoma virus. The pro-p21 proteins were detected in free cytosol, and the processed products were associated with plasma membrane. The intracellular half-life of p21 proteins was determined by pulse-labeling and chasing in the presence of excess unlabeled methionine. Although both p21 proteins of EJ and the normal c-ras genes which are not phosphorylated have a half-life of 20 h, the viral p21 protein of Harvey murine sarcoma virus which includes a phosphorylated form is much more stable in cells, having a half-life of 42 h, apparently due to phosphorylation.
Mol Cell Biol 1984 Aug
PMID:Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs. 609 27


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