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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated a high incidence of ras mutation in thyroid follicular (epithelial) cell neoplasms and showed that expression of mutant ras is a potent mitogenic stimulus for normal human follicular cells in culture. Here we show that induction of cell proliferation in primary follicular cells by a mutant human Ha-ras (val 12) expressed from a retroviral vector was absolutely dependent on the presence of serum growth factors. Induction of DNA synthesis showed partial dependence. Mutant ras-induced growth was also inhibited by exposure to phorbol ester at concentrations sufficient to downregulate protein kinase C. More importantly, we observed an unexpected toxic effect of phorbol ester in this system that was specific to cells expressing mutant ras. This has potential significance both for elucidating the basic mechanism of ras action in epithelial cells and also as a pointer to a novel therapeutic strategy.
Mol Carcinog 1992
PMID:Effect of serum growth factors and phorbol ester on growth and survival of human thyroid epithelial cells expressing mutant ras. 155 11

Renal mesenchymal tumors induced in F344 rats with methyl(methoxymethyl)nitrosamine (DMN-OMe) have previously been shown by our laboratory to contain transforming Ki-ras sequences, activated most commonly by a variety of codon 12 mutations. Further sequence analysis of the one DMN-OMe-induced tumor with transforming Ki-ras sequences detected by NIH 3T3 transfection assay but with no mutation in codon 12 detected by selective oligonucleotide hybridization has now revealed an activating point mutation in codon 63. The observed GAG----AAG transition in codon 63, which replaces glutamic acid with lysine, was the only detectable mutation in exon 1 and 2 hotspot regions of Ki-ras in this tumor. The same mutation was also detected in Ki-ras sequences derived from first- and second-cycle transformants in NIH 3T3 transfection assays. Although random mutagenesis studies of cloned Ha-ras sequences by Fasano et al. (Proc Natl Acad Sci USA 81:4008-4012, 1984) had already indicated that GAG----AAG mutations in codon 63 of ras are transforming, this is the first demonstration of the natural occurrence of this particular activating mutation in a tumor.
Mol Carcinog 1992
PMID:Activating point mutation in Ki-ras codon 63 in a chemically induced rat renal tumor. 155 12

Twenty-five mouse lung tumors induced by a single urethan treatment in female A/J, BALB/c, and (A/J x C3H/He)F1 (AC3) mice were analyzed for the presence of mutations at codon 61 of the Ki-ras gene and for the expression of the surfactant protein A (SP-A), retinoblastoma (Rb), growth arrest-specific-3 (gas-3), p53, c-myc, and thymidylate synthase (TS) genes. Ki-ras codon 61 mutations were detected in 22 of 25 tumor samples without differences among strains. In comparison with normal lungs, all the tumors showed increased SP-A mRNA levels, indicating their derivation from alveolar type II pneumocytes or Clara cells. Rb and gas-3 transcripts were instead found in all tumors at about tenfold and about 20-fold reduced levels, respectively. No apparent structural alterations or loss of heterozygosity at the Rb locus was detected in any tumors. The p53 mRNA was observed without variation in quantity or size in lung tumors and normal tissue. A threefold to fivefold c-myc overexpression was observed, without amplification of the gene. TS expression was only slightly increased, indicating no great differences in cell proliferation between lung tumors and normal tissue. Our data suggest that the pathogenesis of urethan-induced lung tumors in mice involves specific and recurrent molecular alterations (Ki-ras mutations, decrease of Rb and gas-3 expression, and increase of c-myc expression) that could represent different steps in lung carcinogenesis.
Mol Carcinog 1992
PMID:Multiple molecular alterations in mouse lung tumors. 155 14

A large variety of proto-oncogenes are known to be of key importance in cellular growth and differentiation during embryonic development. Using quantitative in situ hybridization, we studied in detail the levels of the proto-oncogenes Ha-ras and c-myc mRNA in embryos and extraembryonic tissues (maternal and embryonic placentas, trophoblast, and endometrial epithelium) during prenatal life of rabbit. cDNA probes encoding for Ha-ras (fragment Kpn 1-BstE II of 883 bp) and c-myc (fragment Pst 1-Pst 1 of 490 bp) were used to detect specific transcripts in fixed cryostat sections. High levels of Ha-ras and c-myc mRNA were detected in the rabbit embryo as well as in the decidua and in the trophoblast as early as day 9 of gestation. At 12 and 15 days of gestation, Ha-ras and c-myc mRNA levels decreased in both embryonic and maternal placenta while in the embryo a significant increase of Ha-ras and c-myc expression was detected with particular evidence in the central nervous system. Finally, at 25 days of gestation the expression of the two proto-oncogenes, Ha-ras and c-myc, was greatly decreased in both the embryo and extraembryonic tissues, and was undetectable by 30 days of gestation. These results show that in rabbit the expression of the two proto-oncogenes Ha-ras and c-myc is localized in the same tissues with similar intensity and follows an unparallel temporal modulation in the embryo and in the extraembryonic tissues during prenatal development.
Mol Reprod Dev 1992 Jan
PMID:Ontogeny of Ha-ras and c-myc mRNA levels in rabbit embryo and extraembryonic tissues by quantitative in situ hybridization. 156 21

Sec4, a GTP-binding protein of the ras superfamily, is required for exocytosis in the budding yeast Saccharomyces cerevisiae. To test the role of GTP hydrolysis in Sec4 function, we constructed a mutation, Q-79----L, analogous to the oncogenic mutation of Q-61----L in Ras, in a region of Sec4 predicted to interact with the phosphoryl group of GTP. The sec4-leu79 mutation lowers the intrinsic hydrolysis rate to unmeasurable levels. A component of a yeast lysate specifically stimulates the hydrolysis of GTP by Sec4, while the rate of hydrolysis of GTP by Sec4-Leu79 can be stimulated by this GAP activity to only 30% of the stimulated hydrolysis rate of the wild-type protein. The decreased rate of hydrolysis results in the accumulation of the Sec4-Leu79 protein in its GTP-bound form in an overproducing yeast strain. The sec4-leu79 allele can function as the sole copy of sec4 in yeast cells. However, it causes recessive, cold-sensitive growth, a slowing of invertase secretion, and accumulation of secretory vesicles and displays synthetic lethality with a subset of other secretory mutants, indicative of a partial loss of Sec4 function. While the level of Ras function reflects the absolute level of GTP-bound protein, our results suggest that the ability of Sec4 to cycle between its GTP and GDP bound forms is important for its function in vesicular transport, supporting a mechanism for Sec4 function which is distinct from that of the Ras protein.
Mol Cell Biol 1992 May
PMID:Hydrolysis of GTP by Sec4 protein plays an important role in vesicular transport and is stimulated by a GTPase-activating protein in Saccharomyces cerevisiae. 156 38

We investigated the mechanism of radiation induction of murine thymic lymphomas by studying the characteristics of primary x-ray-induced thymic lymphoma (PXTL) cell lines and of their oncogene-induced, progressed progeny. It is widely thought that proto-oncogene alterations are associated with the induction of murine lymphomas; however, few, if any primary murine radiation-induced lymphomas possess (proto-)oncogene alterations. Independently derived cell lines grown directly (i.e., without in vivo transplantation) from thymic lymphomas of irradiated C57BL/6 mice possess the properties of immortalized pre-T cells and lack many of the characteristics of "tumor cells". PXTL cells are poorly tumorigenic upon transplantation, do not clone in methylcellulose cultures, are growth factor dependent and autocrine, and lack consistent chromosome and oncogene abnormalities. However, the thymic lymphomas are malignant and cause the death of each afflicted mouse. PXTL cells expressed two immunologically distinct forms of the tumor suppressor protein p53 that have moderately increased stability (t1/2 = 1 h) when compared with p53 of normal splenic T lymphocytes. Early PXTL cells could progress in vitro to a fully tumorigenic phenotype after infection with retroviruses encoding the c-myc and v-ras oncogenes. Progressed T-lymphoma cells acquired growth factor independence, a highly transplantable and tumorigenic phenotype, and the ability to quantitatively clone in methylcellulose cultures. Progressed lymphoma cells coordinately downregulated the expression of five T-cell differentiation markers, upregulated the expression of CD44 (Pgp-1), and harbored vastly elevated levels of two immunologically distinct forms of p53. Our results suggest that the early thymic lymphomas consist of differentiation-inhibited, immortal pre-T cells that are precursors to progressed, fully tumorigenic T-lymphoma cells.
Mol Carcinog 1992
PMID:Association of induction of a fully tumorigenic phenotype in murine radiation-induced T-lymphoma cells with loss of differentiation antigens, gain of CD44, and alterations in p53 protein levels. 158 48

Differential screening of a cDNA library was used to isolate genes differentially expressed in a nontumorigenic clone and a ras-transformed variant of the human teratocarcinoma cell line PA-1. The RNA transcript for one of the cDNA clones that we identified was expressed at a 25-fold higher level in the ras-transformed PA-1 cells than in the nontumorigenic PA-1 cells. DNA sequence analysis of this clone showed that it had 86% nucleic acid homology to the mouse LLRep3 gene and only differed at a single amino acid codon (codon 198), which is changed from serine in LLRep3 to threonine in this cDNA clone. The rat ribosomal S2 protein is closely related to the yeast omnipotent informational suppressor SUP44, which encodes the yeast ribosomal protein S4; to the mouse protein LLRep3; and to the human cDNA clone we describe in this report. We therefore concluded that this clone codes for the human ribosomal S2 protein. In situ hybridization experiments revealed that expression of this gene was elevated in cultured human head and neck squamous cell carcinomas compared with normal keratinocytes. In situ hybridization experiments also demonstrated that expression of this gene was elevated in histological sections of human premalignant leukoplakia, head and neck squamous cell carcinomas, and colon and breast cancers compared with the adjacent normal tissues. S2 expression may be a useful diagnostic or prognostic marker for grading human tumors.
Mol Carcinog 1992
PMID:Elevated expression of the ribosomal protein S2 gene in human tumors. 158 49

We previously found that the T24 Ha-ras oncogene induces metastatic ability in NIH 3T3 cells and that this change depends on expression of the ras oncogene. As part of our studies on mechanisms by which ras may induce metastasis, we investigated expression and activity of two cysteine proteinases, cathepsin L (major excreted protein) and cathepsin B, as well as cysteine proteinase inhibitor activity, in ras-transformed NIH 3T3 cells. In a series of cel lines that expressed differing amounts of ras, we found a good correlation between levels of ras expression and cathepsin L expression (r = 0.80). There was also a good correlation between secreted procathepsin L protein levels and experimental metastatic ability (r = 0.88). We found a similar but less strong association between cathepsin B levels and metastatic ability in these cells (r = 0.76 and r = 0.72 for 2.2-kb and 4.1-kb transcripts, respectively). Functional cathepsin L plus B activity (both secreted and cell-associated) was found to be higher in ras-transformed cells and was dependent on cell confluency in culture. Coupled with increased expression and activity of cysteine proteinases, ras-transformed NIH 3T3 cells showed reduced cysteine proteinase inhibitor activity. We conclude that the balance between expression of cysteine proteinases and their inhibitors may be coregulated by ras expression. Our results suggest that ras-induced increases in production of degradative enzymes such as cathepsins L and B, along with decreased activities of their inhibitors, may contribute to the increased malignant properties of ras-transformed NIH 3T3 cells.
Mol Carcinog 1992
PMID:Increased expression of cathepsins L and B and decreased activity of their inhibitors in metastatic, ras-transformed NIH 3T3 cells. 158 50

The CDC25 gene product of the yeast Saccharomyces cerevisiae has been shown to be a positive regulator of the Ras protein. The high degree of homology between yeast RAS and the mammalian proto-oncogene ras suggests a possible resemblance between the mammalian regulator of Ras and the regulator of the yeast Ras (Cdc25). On the basis of this assumption, we have raised antibodies against the conserved C-terminal domain of the Cdc25 protein in order to identify its mammalian homologs. Anti-Cdc25 antibodies raised against a beta-galactosidase-Cdc25 fusion protein were purified by immunoaffinity chromatography and were shown by immunoblotting to specifically recognize the Cdc25 portion of the antigen and a truncated Cdc25 protein, also expressed in bacteria. These antibodies were shown both by immunoblotting and by immunoprecipitation to recognize the CDC25 gene product in wild-type strains and in strains overexpressing Cdc25. The anti-Cdc25 antibodies potently inhibited the guanyl nucleotide-dependent and, approximately 3-fold less potently, the Mn(2+)-dependent adenylyl cyclase activity in S. cerevisiae. The anti-Cdc25 antibodies do not inhibit cyclase activity in a strain harboring RAS2Val-19 and lacking the CDC25 gene product. These results support the view that Cdc25, Ras2, and Cdc35/Cyr1 proteins are associated in a complex. Using these antibodies, we were able to define the conditions to completely solubilize the Cdc25 protein. The results suggest that the Cdc25 protein is tightly associated with the membrane but is not an intrinsic membrane protein, since only EDTA at pH 12 can solubilize the protein. The anti-Cdc25 antibodies strongly cross-reacted with the C-terminal domain of the Cdc25 yeast homolog, Sdc25. Most interestingly, these antibodies also cross-reacted with mammalian proteins of approximately 150 kDa from various tissues of several species of animals. These interactions were specifically blocked by the beta-galactosidase-Cdc25 fusion protein.
Mol Cell Biol 1992 Jun
PMID:Anti-Cdc25 antibodies inhibit guanyl nucleotide-dependent adenylyl cyclase of Saccharomyces cerevisiae and cross-react with a 150-kilodalton mammalian protein. 158 63

Members of the Myc family of proteins share a number of protein motifs that are found in regulators of gene transcription. Conserved stretches of amino acids found in the N-terminal transcriptional activation domain of c-Myc are required for cotransforming activity. Most of the Myc proteins contain the basic helix-loop-helix zipper (bHLH-Zip) DNA-binding motif which is also required for the cotransforming activity of c-Myc. L-Myc, the product of a myc family gene that is highly amplified in many human lung carcinomas, was found to cotransform primary rat embryo cells with an activated ras gene. However, L-Myc cotransforming activity was only 1 to 10% of that of c-Myc (M. J. Birrer, S. Segal, J. S. DeGreve, F. Kaye, E. A. Sausville, and J. D. Minna, Mol. Cell. Biol. 8:2668-2673, 1988). We sought to determine whether functional differences between c-Myc and L-Myc in either the N-terminal or the C-terminal domain could account for the relatively diminished L-Myc cotransforming activity. Although the N-terminal domain of L-Myc could activate transcription when fused to the yeast GAL4 DNA-binding domain, the activity was only 5% of that of a comparable c-Myc domain. We next determined that the interaction of the C-terminal bHLH-Zip region of L-Myc or c-Myc with that of a Myc partner protein, Max, was equivalent in transfected cells. A Max expression vector was found to augment the cotransforming activity of L-Myc as well as that of c-Myc. In addition, a bacterially synthesized DNA-binding domain of L-Myc, like that o c-Myc, heterodimerizes with purified Max protein to bind the core DNA sequence CACGTG. To determine the region of L-Myc responsible for its relatively diminished cotransforming activity, we constructed chimeras containing exons 2 (constituting activation domains) and 3 (constituting DNA-binding domains) of c-Myc fused to those of L-Myc. The cotransforming potencies of these chimeras were compared with those of full-length L-Myc of c-Myc in rat embryo cells. The relative cotransforming activities suggest that the potencies of the activation domains determine the cotransforming efficiencies for c-Myc and L-Myc. This correlation supports the hypothesis that the Myc proteins function in neoplastic cotransformation as transcription factors.
Mol Cell Biol 1992 Jul
PMID:Activation domains of L-Myc and c-Myc determine their transforming potencies in rat embryo cells. 162 Jan 20


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