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Query: UNIPROT:P06889 (Mol)
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Expression of a mutant H-ras gene confers a transformed phenotype to rat-1 fibroblasts which is basically independent of exogenous growth factors (GFs). Rat-1 cells induced to express high levels of the normal H-ras gene were also found to display a transformed phenotype. In contrast to cells expressing mutant H-ras, these cells were dependent on GFs. We used this difference in GF dependence to analyze a possible involvement of exogenous GFs in H-ras function. Compared with untransformed rat-1 cells, cells overexpressing normal H-ras displayed an elevated response toward insulinlike growth factor 1 (IGF-1), insulin, and bombesin and an increased sensitivity toward phosphatidic acids. It was found that 8-bromo-cyclic AMP inhibited the responses to all GFs in rat-1 cells but had no effect on mutant-H-ras-transformed cells. In cells overexpressing normal H-ras, 8-bromo-cyclic AMP inhibited the responses to all GFs except those to insulin and IGF-1. This implies that overexpression of normal H-ras in the presence of insulin/IGF-1 is functionally similar to the expression of mutant H-ras, since mutant H-ras can circumvent this block by itself. These and other results strongly suggest a functional linkage between insulin/IGF-1 and normal p21 H-ras.
Mol Cell Biol 1989 Oct
PMID:Possible involvement of normal p21 H-ras in the insulin/insulinlike growth factor 1 signal transduction pathway. 255 88

Purified membrane-bound Na,K-ATPase incubated with cobalt-tetrammine-ATP [Co(NH3)4ATP], which is a stable MgATP complex analog, shows two new types of membrane crystals, a new p21 form and a p4 form. The building blocks of the crystalline arrays correspond to (alpha beta)2 dimers of the enzyme protein suggesting that alpha-alpha interaction may be important in the pumping process.
J Ultrastruct Mol Struct Res 1989 Dec
PMID:Two-dimensional crystalline arrays of Na,K-ATPase with new subunit interactions induced by cobalt-tetrammine-ATP. 256 64

In this report we describe the expression of the ras proto-oncogene p21 protein in various tissues during normal fetal development. Conventional, formalin fixed and paraffin-embedded sections of normal organs were examined from fetuses ranging 9 to 42 weeks of gestation. Immunohistochemical localization of ras p21 was accomplished using the broadly reactive, mouse monoclonal antibodies RAP-5 and Y13-259. The monoclonal antibody DWP, which is specific for a mutated form of ras p21 having a valine/cysteine at amino acid position 12, was also used. Detectable expression of the p21 protein was seen at different time periods during fetal development depending on the tissue. The expression of ras p21 (as detected by RAP-5 and Y13-259) was noted in a wide range of cell types and tissues; intense immunostaining was noted in epithelial cells of the gastrointestinal tract, exocrine and endocrine pancreas, renal tubules and transitional urotheliem, as well as in other tissues. This immunostaining generally, but not invariably, corresponded with patterns previously reported in benign and/or malignant neoplasms of adult tissues. In most instances ras p21 expression, when present, occurred during periods of rapid growth in given organ systems. However, some actively proliferating fetal tissues such as thymus and spleen, failed to express detectable ras p21 suggesting that factors other than cell cycle may influence its expression. No reactivity with DWP was noted in any of the tissues, suggesting that the mutated forms detected by this monoclonal antibody are not expressed during normal human embryogenesis. These data show that there is regulated expression, and broad distribution of this gene product in normal developing human fetal tissue.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Expression of ras oncogene p21 during human fetal development as determined by monoclonal antibodies RAP-5, Y13-259, and DWP. 256 31

In this study we examined 214 cases of primary human pulmonary neoplasms for the expression of a mutated form of the ras oncogene p21 product, recognized by the monoclonal antibody (MCA) DWP. Adjacent serial sections from these same cases had previously been used to demonstrate the frequency of ras p21 expression using the broadly reactive anti-ras p21 MCA RAP-5. Confirmation of the increased expression of p21 was accomplished using MCA Y13-259. The use of adjacent tissue sections from these cases allows the direct comparison of the expression of the mutated and non-mutated forms of ras p21. If reactivity with DWP would prove to be significantly more restrictive than that of the "pan" ras MCAs, RAP-5 and Y13-259, it would lend support to the possibility that DWP (and similar MCAs which detect other specific mutations) could be used to define subsets of these neoplasms based on their specific ras p21 phenotype. Since one would anticipate that the valine/cysteine substitution at position 12 of the ras p21 would occur at only low frequencies in human tumors, our results with DWP are consistent with this hypothesis. As previously reported, RAP-5 reacted with a high proportion of lung tumors (100/214 or 47%). In this report, we demonstrate the selective expression of the mutation recognized by the MCA DWP in only 5% of these same tumors (13/214), and that the expression of this mutated form is not restricted to any of the conventional histological subclasses of pulmonary neoplasms.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Immunohistochemical analysis of normal and mutated ras oncogene p21 expression in human pulmonary and pleural neoplasms. 256 85

The cDNA coding for mouse and human ras p21 GTPase-activating protein (GAP) was isolated; the deduced amino acid sequences share over 96% homology with that previously determined for bovine brain GAP. Both the mouse and human GAP cDNAs were used as probes for the chromosomal localization of this gene. The locus designations for the gene encoding GAP in human and mouse are RASA and Rasa (for ras-activating protein), respectively. By somatic cell hybrid analysis and in situ chromosomal hybridization, we have assigned the RASA gene to human chromosome band 5q13.3. In addition, with somatic cell genetics and linkage analysis in recombinant inbred mouse strains, the murine Rasa gene was localized to the distal end of mouse chromosome 13. These assignments place the gene encoding GAP in a known conserved syntenic region.
Somat Cell Mol Genet 1989 Nov
PMID:Chromosome localization and cDNA sequence of murine and human genes for ras p21 GTPase activating protein (GAP). 257

Infection of mouse embryos at 8 days of gestation with a replication-defective retrovirus carrying the human c-Ha-ras-1 oncogene led to efficient and rapid induction of hyperplastic lesions. Twenty-four percent of viable off-spring developed abnormal growths after infection with purified virus. The lesions contained a single integrated provirus and produced viral RNA and the Ha-ras oncogene product (p21). The latency period between the time of infection and appearance of the lesions suggested that secondary alterations in addition to activated ras were necessary for neoplasms to develop. The earliest and most abundant growths were cutaneous and appeared from 4 to 36 weeks of age, with a median of 4 weeks of age. A number of subcutaneous lesions also developed over the same time span but at a median of 18 weeks of age. The rapid development of cutaneous lesions in response to transduction of the ras oncogene contrasts with other studies in which adult skin required secondary treatment with promoters prior to ras induction of epithelial hyperplasia. These results demonstrate that infection of midgestation mouse embryos allows rapid analysis of oncogene potency in skin.
Mol Cell Biol 1989 Jan
PMID:Retroviral transduction of the human c-Ha-ras-1 oncogene into midgestation mouse embryos promotes rapid epithelial hyperplasia. 264 34

The catalytic domain (amino acid residues 1 to 166) of the human ras-oncogene product p21 complexed with the GTP analogues beta,gamma-imido-GTP (GMPPNP), beta,gamma-methylene-GTP (GMPPCP), and guanosine-5'-(gamma-thiotriphosphate) (GTP gamma S) have been been crystallized. Crystals of the GMPPNP and GMPPCP complexes are well suited for high resolution X-ray crystallography. They belong to space group P3(1)21 (or its enantiomorph P3(2)21) with unit cell axes a=b=40.3 A and c = 162.2 A.
J Mol Biol 1989 Mar 05
PMID:Crystallization and preliminary X-ray analysis of the human c-H-ras-oncogene product p21 complexed with GTP analogues. 264 86

The modulation of gap junctional intercellular communication (GJIC) plays an important role during tumor promotion. Several tumor-promoting agents are known to inhibit this form of cellular coupling. In addition, tumor cells and cells expressing certain oncogenic products have been shown to exhibit inhibited or reduced GJIC. The Ha-ras oncogene is expressed in a wide variety of human tumors from different tissues. Its p21 product is a membrane-bound polypeptide, the function of which is not fully characterized. We tested the effects of the expression of the human c-Ha-ras-1 oncogene, derived from the EJ/T4 bladder carcinoma cell line, on the ability of the Chinese hamster V79 cells to conduct gap junctional communication. The junctional competence was studied by two different methods, the scrape-loading/dye transfer technique and the metabolic cooperation assay. The results indicate a strong correlation between the expression of p21 ras protein and the inhibition of gap junctional function. Assuming that reversible inhibition of intercellular communication plays a role during tumor promotion and stable inhibition during the tumor progression phase of carcinogenesis, our data suggest that, while chemical tumor promoters and the ras oncogenes might work by different biochemical mechanisms, they both affect a critical cellular function; namely, GJIC.
Mol Carcinog 1989
PMID:Potential role of the human Ha-ras oncogene in the inhibition of gap junctional intercellular communication. 267 3

Azatyrosine [L-beta-(5-hydroxy-2-pyridyl)-alanine], an antibiotic isolated from Streptomyces chibanensis, inhibited the growth of NIH 3T3 cells transformed by the activated human c-Ha-ras gene but did not significantly inhibit the growth of normal NIH 3T3 cells. Surprisingly, upon treatment with azatyrosine most of the transformed cells apparently became normal. These apparently normal cells, named revertant cells, grew in the presence of azatyrosine and stopped growing when they reached confluency, and their normal phenotype persisted during prolonged culture in the absence of azatyrosine. The revertant cells did not grow in soft agar and scarcely proliferated in nude mice. The human c-Ha-ras gene present in transformed NIH 3T3 cells was still present in the revertant cells and was expressed to the same extent as in the original transformed cells, producing the same amount of activated p21. Treatment with azatyrosine caused similar conversion of NIH 3T3 cells transformed by activated c-Ki-ras, N-ras, or c-raf to apparently normal cells, but NIH 3T3 cells transformed by hst or ret were not exclusively converted by azatyrosine. Human pancreatic adenocarcinoma cells, which are known to contain an amplified activated c-Ki-ras gene and an amplified c-myc gene, were also converted to flat and giant revertant cells by treatment with azatyrosine.
Mol Carcinog 1989
PMID:Permanent conversion of mouse and human cells transformed by activated ras or raf genes to apparently normal cells by treatment with the antibiotic azatyrosine. 267 4

We review the use of functional assays for the ras protein, p21, that have allowed us to screen for mutant ras genes encoding proteins defective in either interactions with guanine nucleotides or transforming activity. GTP binding and GTP-dependent autokinase activities were assayed directly on lysed bacterial colonies expressing p21. Mutants encoding ras proteins deficient in these activities were isolated after randomly mutagenizing a v-rasH expression vector. Transformation defective mutants were isolated by randomly mutagenizing a v-rasH retroviral shuttle vector. NIH cells were then infected with a stock of nonreplicating mutagenized retroviruses and nontransformed infected colonies were isolated. The mutant ras genes were then rescued from these cells for analysis. Characterization of these mutants defines domains of p21 involved in both biochemical and biological activities and addresses the role of guanine nucleotide binding in p21 function.
Mol Endocrinol 1987 Feb
PMID:Structure/function analysis of ras using random mutagenesis coupled with functional screening assays. 284 63


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