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Query: UNIPROT:P06889 (Mol)
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Rat neoplasms induced by methylating carcinogens frequently contain ras genes activated by a single point mutation. Rat prostatic tumors induced by a combination of a single injection of N-methyl-N-nitrosourea (MNU) and long-term treatment with testosterone were examined for the presence of such activating point mutations in ras genes. These tumors, which arose exclusively in the dorsolateral prostate, included both adenocarcinomas and sarcomas. Activating mutations in codon 12 of the Ki-ras gene were found in 7 of 10 carcinomas and 4 of 5 sarcomas, using selective oligonucleotide hybridization analysis of DNA amplified by the polymerase chain reaction (PCR). However, no mutated Ha-ras oncogenes were detected. The presence of PCR-engineered Hphl restriction sites created by the existence of a G35----A mutation in the rat Ki-ras oncogene identified the mutation as a GC----AT transition at the second position of codon 12. Production of O6-methylguanine adducts in the Ki-ras codon 12 followed by base mispairing during replicative DNA synthesis is thus the likely molecular mechanism of initiation of prostatic carcinogenesis by MNU in the rat. Three of the four sarcomas positive for the Ki-ras G35----A mutation were immunohistochemically defined as of Schwann cell origin, indicating that involvement of the ras gene family is possible in tumorigenesis of this cell lineage. Loss of the wild-type Ki-ras allele was also observed in all four of these sarcomas.
Mol Carcinog 1991
PMID:Frequent activation of the Ki-ras oncogene at codon 12 in N-methyl-N-nitrosourea-induced rat prostate adenocarcinomas and neurogenic sarcomas. 168 Mar 40

Transient transfections of mutated MMTV LTRs, driving the luciferase reporter gene, have shown the presence of at least one cis-acting element cooperating with the GREs. Studies of the chromatin structure of two glucocorticoid-regulated promoters, the mouse mammary tumor virus (MMTV) long terminal repeat (LTR), a retroviral promoter, and the rat tyrosine aminotransferase (TAT) promoter, demonstrate that both DNAs are organized into precisely positioned nucleosomes. Hormonal activation of transcription is accompanied by structural changes of one (MMTV LTR) or two (TAT promoter) nucleosomes associated with the hormone-response elements (HREs). These changes can be visualized by the appearance of DNasel hypersensitive sites. Association of the hormone-receptor complex with the nucleus is necessary to induce the DNasel hypersensitive site and to maintain transcription, but is not necessary to maintain DNasel hypersensitivity. Anti-hormones, even when able to promote a strong binding of the receptor to the nucleus, are unable to induce the chromatin structural change. Using cell lines containing approx. 200 copies of a MMTV LTR/Hv-ras chimeric construct, we have demonstrated a strong, hormono-independent nuclear matrix interaction of sequences located just upstream and downstream of the ras coding sequences.
J Steroid Biochem Mol Biol 1991
PMID:Chromatin structure of hormono-dependent promoters. 168 63

We studied the effects of transfection of the normal c-Ha-ras gene, rasGly-12, and its oncogenic mutant, rasVal-12, on expression of the alpha-fetoprotein (AFP) and albumin genes in a human hepatoma cell line, HuH-7. The mutant and, to a lesser extent, the normal ras gene caused reduction of the AFP mRNA but not the albumin mRNA level in transfected HuH-7 cells. Cotransfection experiments with a rasVal-12 expression plasmid and a chloramphenicol acetyltransferase reporter gene fused to AFP regulatory sequences showed that rasVal-12 suppressed the activity of enhancer and promoter regions containing A + T-rich sequences (AT motif). In contrast, rasVal-12 did not affect the promoter activity of the albumin and human hepatitis B virus pre-S1 genes even though these promoters contain homologous A + T-rich elements. ras transfection appeared to induce phosphorylation of nuclear proteins that interact with the AFP AT motif, since gel mobility analysis revealed the formation of slow-moving complexes which was reversed by phosphatase treatment. However, similar changes in complex formation were observed with the albumin and hepatitis B surface antigen pre-S1 promoters. Therefore, this effect alone cannot explain the specific down regulation of the AFP promoter and enhancer activity. ras-mediated suppression of the AFP gene may reflect the process of developmental gene regulation in which AFP gene transcription is controlled by a G-protein-linked signal transduction cascade triggered by external growth stimuli.
Mol Cell Biol 1990 Apr
PMID:c-Ha-ras down regulates the alpha-fetoprotein gene but not the albumin gene in human hepatoma cells. 169 Aug 41

The suppression of growth arrest-specific (gas) gene expression by serum appeared to be independent of protein synthesis, but expression in resting cells was sensitive to 2-aminopurine, an inhibitor of intracellular protein kinases. Although accumulation of gas gene mRNA was reduced by serum, nuclear transcription of the gas-2, -3, and -5 genes was observed in serum-stimulated cells, indicating that posttranscriptional events may regulate mRNA levels. Growth induction by serum, on the other hand, led to suppression of transcription of the gas-1 gene. Cell cycle regulation and the serum response of gas-1 were lost in ras-transformed cells.
Mol Cell Biol 1990 Apr
PMID:Regulation of expression of growth arrest-specific genes in mouse fibroblasts. 169 Aug 45

Several lines of evidence have suggested that c-fos may act downstream from c-Ha-ras in a growth-regulatory signal transduction pathway. We used antisense RNA to inhibit c-fos gene expression and investigated the effects of diminished c-fos expression on the phenotypes induced by the EJ c-Ha-ras oncogene in NIH 3T3 cells. Immunofluorescent staining demonstrated that the antisense RNA caused a marked reduction in the amount of c-fos protein expressed following serum stimulation. EJ cells containing antisense-fos RNA continued to overexpress ras and remained capable of proliferating in vitro. However, the antisense-fos RNA caused a partial reversion of the major transformed phenotypes of EJ cells, including a restoration of both density-dependent growth arrest and the ability to be rendered quiescent by serum deprivation, a reversion to a flat morphology, inhibition of anchorage-independent growth, and inhibition of tumorigenicity in nude mice. Our results indicate that inhibition of c-fos expression, to a level still supporting in vitro proliferation, prevents the transforming effects of the ras oncogene; they thus provide additional evidence for the participation of c-fos in ras-regulated signal transduction pathways.
Mol Cell Biol 1990 Apr
PMID:Antisense-fos RNA causes partial reversion of the transformed phenotypes induced by the c-Ha-ras oncogene. 169 Aug 47

To overcome the difficulty of assessing oncogene action in human epithelial cell types, such as thyroid, which have limited proliferative potential in culture, we have explored the use of temperature-sensitive (ts) mutants of simian virus 40 (SV40) early region to create conditionally immortalized epithelial cell lines. Normal primary cultures of human thyroid follicular cells were transfected with a plasmid containing the SV40 early region from mutant tsA58. Expanding epithelial colonies were observed after 2 to 3 months, all of which grew to greater than 200 population doublings without crisis. All showed tight temperature dependence for growth. After switch-up to the restrictive temperature (40.5 degrees C), no further increase in cell number was seen after 1 to 2 days. However, DNA synthesis declined much more slowly; the dissociation from cell division led to marked polyploidy. Viability was maintained for up to 2 weeks. Introduction of an inducible mutant ras gene into ts thyroid cells led, as expected, to morphological transformation at the permissive temperature when ras was induced. Interestingly, this was associated with a marked reduction in net growth rate. At the restrictive temperature, induction of mutant ras caused rapid cell death. These results demonstrate the utility of a ts SV40 mutant to permit the study of oncogene action in an otherwise nonproliferative target cell and reveal important differences in the interaction between ras and SV40 T in these epithelial cells compared with previously studied cell types.
Mol Cell Biol 1990 Oct
PMID:Conditional immortalization of human thyroid epithelial cells: a tool for analysis of oncogene action. 169 30

Sporulation, spore germination, and yeast-hypha dimorphism in the filamentous fungus Mucor racemosus provide useful model systems to study cell development in eucaryotic cells. Three RAS genes (MRAS1, MRAS2, and MRAS3) from M. racemosus have been cloned, and their nucleotide sequences have been determined. The predicted amino acid sequences and the sizes of the three MRAS proteins exhibit a high degree of similarity with other ras proteins, including that encoded by H-ras, which have been implicated in regulation of proliferation and development in eucaryotic cells by mediating signal transduction pathways. The MRAS proteins show conservation of functional domains proposed for ras proteins, including guanine nucleotide interaction domains, an effector domain, a binding epitope for neutralizing antibody Y13-259, and the COOH-terminal CAAX box, which is a site of thiocylation and membrane attachment. Amino acid sequences unique to each MRAS protein occur adjacent to the CAAX box, consistent with the location of the hypervariable region in other ras proteins. Northern (RNA) analysis was used to study expression of the three MRAS genes in relation to cell development. Gene-specific probes for two of these genes, MRAS1 and MRAS3, hybridized to different 1.3-kb mRNA transcripts. The accumulation of these transcripts depended on the developmental stage, and this pattern was different between the two MRAS genes. No transcript for MRAS2 was detected in the developmental stages examined. The unique patterns of MRAS transcript accumulation suggest that individual MRAS genes and proteins may play distinct roles in cell growth or development.
Mol Cell Biol 1990 Dec
PMID:Expression of a gene family in the dimorphic fungus Mucor racemosus which exhibits striking similarity to human ras genes. 170 Oct 21

GTPase-activating protein (GAP) is a cytosolic protein that stimulates the rate of hydrolysis of GTP (GTP to GDP) bound to normal p21ras, but does not catalyze the hydrolysis of GTP bound to oncogenic, activated forms of the ras protein. Transformation of cells with v-src or activated transforming variants of c-src or stimulation of cells with epidermal growth factor resulted in the stable association of GAP with two tyrosine-phosphorylated cellular proteins of 64 kDa (p64) and 190 kDa (p190). Analysis of GAP immune complexes isolated from extracts of metabolically labeled src-transformed cells and epidermal growth factor-stimulated cells indicated that tyrosine phosphorylation of p64 and p190 appeared to be coincident with the stable association of these proteins with GAP. Quantitation of the amount of p64 associated with GAP in v-src-transformed cells, however, indicated that only 15 to 25% of tyrosine-phosphorylated p64 was found in complex with GAP. Mutations within the SH2 region of pp60src that render activated pp60src defective for transformation inhibited the efficient formation of complexes between GAP and the tyrosine-phosphorylated forms of p64 and p190. From these data, we suggest that tyrosine phosphorylation and stable association of p64 with GAP is an important step in mediating cellular signaling through the p21ras-GAP pathway.
Mol Cell Biol 1991 Feb
PMID:Transformation by pp60src or stimulation of cells with epidermal growth factor induces the stable association of tyrosine-phosphorylated cellular proteins with GTPase-activating protein. 170 33

Cultured mouse keratinocytes can be initiated in vitro by the introduction of a v-rasHa gene by viral transduction. Previous studies indicated that v-rasHa-transduced keratinocytes have a high proliferation rate in medium with 0.05 mM Ca2+ and resist terminal differentiation in medium with greater than 0.1 mM Ca2+, a culture condition in which normal cells mature into squames. The current studies demonstrate that v-rasHa keratinocytes do not express transcripts or protein for epidermal early differentiation markers keratins 1 and 10 when cells are challenged with 0.12 mM Ca2+, which is a signal for expression of these genes in normal cells. Both transcript and protein for the late differentiation marker loricrin are also diminished in v-ras keratinocytes, but filaggrin, also a late differentiation-related gene product, is expressed in nearly normal amounts but at a different Ca2+ optimum. Modification of intracellular Ca2+ with ionomycin failed to restore the expression of any suprabasal keratinocyte markers. In contrast to the effects on normal products of keratinocyte differentiation, the introduction of the v-rasHa gene facilitated the expression of keratins 8 (K8) and 18 (K18). These keratins are characteristic of embryonic cells and cells of simple adult epithelia but not stratified squamous epithelia such as skin. Like normal differentiation markers, the expression of K8 and K18 was dependent both on the v-ras oncogene and the Ca2+ concentration of the culture medium, with greater than 0.1 mM Ca2+ being optimal. At the optimal Ca2+ level, the majority of v-ras keratinocytes expressed K8 and K18 after 96 h, and many cells had reduced amounts of the normal keratinocyte cytokeratin K14. These studies indicate that the v-ras gene causes substantial reprogramming of epidermal physiology, producing an unusual phenotype devoid of early suprabasal markers but at least partially permissive for late marker expression. Furthermore, the Ca2(+)-dependent expression of K8 and K18 suggests that a normal signalling pathway used in keratinocyte differentiation is diverted to an abnormal endpoint.
Mol Carcinog 1990
PMID:The v-ras oncogene inhibits the expression of differentiation markers and facilitates expression of cytokeratins 8 and 18 in mouse keratinocytes. 170 65

The analysis of phosphotyrosine-containing proteins in Rat 1 cells overexpressing either the tyrosine kinase pp60c-src or genetic variants containing alterations in functional and structural domains has led to the identification of three proteins whose tyrosine phosphorylation correlated with pp60src-induced cellular transformation. The tyrosine phosphorylation of one of these proteins, p120, has been previously shown by us and others to coincide with the presence of kinase-activated, membrane-associated pp60src in chicken embryo cells. The second protein was identified as the ras-associated GTPase-activating protein (GAP). The third protein whose tyrosine phosphorylation was markedly elevated in Rat 1 cells expressing activated, membrane-bound forms of pp60src had an apparent molecular mass of 64-67 kDa. The electrophoretic mobility of this protein varied in cells expressing different pp60src variants. The tyrosine-phosphorylated form of p64-67 was present in immune complexes containing GAP, suggesting a stable interaction between these two cellular proteins.
Mol Carcinog 1991
PMID:Tyrosine phosphorylation of three cellular proteins correlates with transformation of rat 1 cells by pp60src. 171 Apr 64


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