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PubMed2006

Single-molecule diffusion reveals similar mobility for the Lck, H-ras, and K-ras membrane anchors.

Recent evidence on the occurrence of small (5-700 nm diameter) lipid microdomains in the exoplasmic leaflet of the plasma membrane has evoked interest in the possibility that similar domains may also be present in the cytoplasmic leaflet of the plasma membrane. However, current knowledge about these "lipid rafts", in live cells is limited. One way to obtain insight into the occurrence and the size of lipid rafts is the use of single-molecule microscopy, which allows one to study the diffusive motion of individual molecules with high positional and temporal accuracy. Using this technique, we compared the diffusion behavior of the Lck membrane anchor, which has a high affinity for lipid rafts, to the diffusion behavior of the K-Ras membrane anchor, which has negligible affinity for rafts and compared the results with those of the H-Ras membrane anchor. Surprisingly, we found only minor differences in the diffusion behavior of the various lipid anchors, indicating that putative cytoplasmic leaflet lipid rafts would have to be small (<137 nm diameter) and do not affect the mobility of membrane-anchored molecules much on timescales up to 60 ms.

3T3 Cells↗

PubMed2005

Eupatilin inhibits proliferation of ras-transformed human breast epithelial (MCF-10A-ras) cells.

Artemisia asiatica Nakai has been used frequently in traditional Asian medicine for the treatment of inflammation and cancer. Eupatilin (5,7-dihydroxy-3',4', 6-trimethoxy-flavone) was shown to be a pharmacologically active ingredient of A. asiatica. In the present study, we found that expression of cyclin D1, a key protein that regulates G1/S progression, was decreased in MCF-10A-ras cells treated with eupatilin. Downregulation of cyclin D1 expression by eupatilin was accompanied by a reduced expression of c-Jun and the DNA binding activity of the transcription factor AP-l. The expression of p21waf1/Cip1 was also decreased by eupatilin treatment in both protein and the mRNA levels. We concluded that the inhibitory effect of eupatilin on p21waf1/Cip1 expression is likely to be associated with the downregulation of cyclin D1 expression and AP-1 activation, which play an important role in the cell cycle arrest of ras-transformed breast epithelial cells.

Cell Line, Transformed↗

PubMedDate not supplied

Effects of benzamidine derivatives on Ha-ras-1 mRNA accumulation in a Chinese hamster cell line transformed with the activated human T24 Ha-ras-1 oncogene.

Tetra benzamidine derivatives were found to inhibit proteinase activity, cell proliferation and accumulation of the Ha-ras-1 mRNA in the FHO6T1-1 Chinese Hamster cell line, transformed with the activated human T24-Ha-ras-1 oncogene. Di- and Tri-benzamidine derivatives were also found to be potent inhibitors of proliferation of FHO6T1-1 cells. These latter compounds could be proposed as useful substrates in the synthesis of drug-conjugated monoclonal antibodies or growth factors.

Amidines↗

PubMed1987

Prognostic implications of expression of the cellular genes myc, fos, Ha-ras and Ki-ras in colon carcinoma.

Messenger RNA levels of the c-fos, c-myc, c-Ha-ras and c-Ki-ras genes were studied in 39 tissue samples obtained from 17 patients undergoing surgery for colon carcinoma and other colon diseases. DNA extracted from the same samples was studied by Southern analysis. The tissues were tumors and grossly normal mucosa from each case and in some instances benign polyps and metastases. Our results indicate: (1) that 50% of cases studied show an increase in expression of at least one of the oncogenes studied; (2) that over-expression is not random, some cases over-expressing several of the genes studied; (3) that the expression pattern of the oncogenes studied varies between primary tumor and metastases; (4) that amplification is a rare event, being limited to one instance in which c-myc was amplified in a metastasis; (5) that cases which exhibit high levels of mRNA in one or more genes studied correlate with biologically aggressive tumors; and (6) that "non-expressors" are at higher risk for local recurrence based on correlations with mucin histochemistry.

Adenocarcinoma↗

PubMed1987

Suppression of tumorigenicity in somatic cell hybrids does not involve quantitative changes in transcription of cellular Ha-ras, Ki-ras, myc, and fos oncogenes.

The transcriptional activity of ten cellular oncogenes was analyzed in somatic cell hybrids that had been obtained after fusion of tumorigenic Chinese hamster cells and normal mouse fibroblasts. The hybrids showed either the tumorigenic or the nontumorigenic phenotype (suppression of tumorigenicity). Out of ten c-onc genes analyzed, four (c-Ha-ras, c-Ki-ras, c-myc, and c-fos) were found to be transcriptionally active at similar levels in tumorigenic as well as in nontumorigenic (suppressed) hybrids. Thus we conclude that suppression of tumorigenicity in Chinese hamster X mouse somatic cell hybrids does not correlate with quantitative changes in expression of these cellular oncogenes. The remaining six cellular oncogenes (c-abl, c-erb A and B, c-fes, c-myb, and c-sis) were not transcriptionally active in these hybrids.

Animals↗

PubMed1985

c-Ha-ras not c-Ki-ras activation in three colon tumour cell lines.

Using the NIH 3T3 transformation assay system, an activated c-Ha-ras transforming gene has been identified in three distinct early passage colon carcinoma cell lines isolated from an invasive, differentiated, adenocarcinoma. The p21 c-Ha-ras gene product from these cell lines displayed an altered electrophorectic mobility and a point mutation in the DNA coding sequence leading to an amino acid substitution at position 12.

Animals↗

PubMed1989

Southern blot analysis of Bcr, N-ras, H-ras, c-myc and myb proto-oncogenes in blast crisis of chronic myelogenous leukemia.

Proto-oncogenes were studied by Southern blotting in 12 patients with chronic myelogenous leukemia in blast crisis (CML). Cytogenetically, all cases had Philadelphia (Ph1) chromosome and 4 had additional chromosomal abnormalities including +8, +19, i(17q), double Ph1. The bcr gene was rearranged in all cases and the region of breakage points were located in the 5.8 kb Bgl II-Bam HI fragment of bcr. In a case with double Ph1 the breakage points of bcr were thought to be different from each other. We analyzed other proto-oncogenes (N-ras, H-ras, c-myc and myb) by Southern blotting, but did not find any abnormalities.

Adult↗

PubMed2006

L-NAME has opposite effects on the productions of S-adenosylhomocysteine and S-adenosylmethionine in V12-H-Ras and M-CR3B-Ras pheochromocytoma cells.

Homocysteine is a sulfur-containing, nonproteinogenic, neurotoxic amino acid biosynthesized during methyl cycles after demethylation of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) and subsequent hydrolysis of SAH into homocysteine and adenosine. Formed homocysteine is either catabolized into cystathionine (transsulfuration pathway) by cystathionine beta-synthase, or remethylated into methionine (remethylation pathway) by methionine synthase. To demonstrate the specificity of Ras-elicited effects on the activity of methyl cycles, wild-type pheochromocytoma PC12, mutant oncogenic rasH gene (MVR) expressing PC12 pheochromocytoma and normal c-rasH stably transfected M-CR3B cells were incubated with the N(omega)-nitro-L-arginine methyl ester (L-NAME), and manumycin, (inhibitors of nitric oxide synthase and farnesyltransferase, respectively). We have found that L-NAME significantly changes the SAM/SAH ratio in both MCR and MVR cells. Moreover, these alterations have reciprocal character; in the MCR cells, the SAM/SAH ratio was raised, whereas in the MVR cells this ratio was decreased. We conclude that depletion of endogenous NO with L-NAME increased the production of SAH only in cells with mutated oncogenic RasH, possibly through enhancement of production of reactive oxygen species (ROS). Oxidative stress can increase cystathionine beta-synthase activity that switches methyl cycles from remethylation into transsulfuration pathway to maintain the intracellular glutathione pool (essential for the redox-regulating capacity of cells) via an adaptive process.

Animals↗

PubMed2005

H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton.

Plasma membrane compartmentalization imposes lateral segregation on membrane proteins that is important for regulating signal transduction. We use computational modeling of immunogold spatial point patterns on intact plasma membrane sheets to test different models of inner plasma membrane organization. We find compartmentalization at the nanoscale level but show that a classical raft model of preexisting stable domains into which lipid raft proteins partition is incompatible with the spatial point patterns generated by the immunogold labeling of a palmitoylated raft marker protein. Rather, approximately 30% of the raft protein exists in cholesterol-dependent nanoclusters, with approximately 70% distributed as monomers. The cluster/monomer ratio (number of proteins in clusters/number of proteins outside clusters) is independent of expression level. H-rasG12V and K-rasG12V proteins also operate in nanoclusters with fixed cluster/monomer ratios that are independent of expression level. Detailed calibration of the immunogold imaging protocol suggests that radii of raft and RasG12V protein nanoclusters may be as small as 11 and 6 nm, respectively, and shows that the nanoclusters contain small numbers (6.0-7.7) of proteins. Raft nanoclusters do not form if the actin cytoskeleton is disassembled. The formation of K-rasG12V but not H-rasG12V nanoclusters also is actin-dependent. K-rasG12V but not H-rasG12V signaling is abrogated by actin cytoskeleton disassembly, which shows that nanoclustering is critical for Ras function. These findings argue against stable preexisting domains on the inner plasma membrane in favor of dynamic actively regulated nanoclusters similar to those proposed for the outer plasma membrane. RasG12V nanoclusters may facilitate the assembly of essential signal transduction complexes.

Actins↗

PubMed2005

An alliance between Ras GTPase-activating protein, filamin C, and Ras GTPase-activating protein SH3 domain-binding protein regulates myocyte growth.

We have previously reported that Ras GTPase-activating protein (RasGAP) is involved in a pathway that regulates total cellular mRNA and protein synthesis in cardiac myocytes. A yeast two-hybrid screen resulted in identification of filamin C (FLN-C) as one of its targets. Knockdown of RasGAP or FLN-C, or severing their interaction, resulted in down-regulation of the RNA polymerase II kinase, cyclin-dependent kinase 7 (Cdk7). This appeared to be provoked by the release of cdk7 mRNA from RasGAP SH3 domain-binding protein, G3BP, and its subsequent degradation. In parallel, myocyte growth was also inhibited. On the other hand, overexpression of RasGAP induced a Cdk7- and FLN-C-dependent growth. Thus, we propose that the physical interaction between RasGAP and FLN-C facilitates an interaction between G3BP and cdk7 mRNA. This results in stabilization of cdk7 mRNA, an increase in its protein, which is required for cell growth.

Actins↗

PubMed1992

Identification of ras and ras-related low-molecular-mass GTP-binding proteins associated with rat lung lamellar bodies.

Recent evidence from genetic experiments in yeast and from studies using guanosine triphosphate (GTP) analogues in mammalian cells suggests a key role for low-molecular-mass GTP-binding proteins (LMM-GBPs) (Mr 19 to 28 kD) in processes of intracellular vesicular sorting and secretion. Assembly and exocytosis of the lamellar body (LB), the secretory organelle of the pulmonary alveolar type 2 pneumocyte, may be regulated by LMM-GBPs. We used [alpha-32P]GTP binding to Western blotted proteins, ultraviolet crosslinking of [alpha-32P]GTP to membrane proteins, immunoblotting with specific antisera, and botulinum exoenzyme C3-catalyzed ADP ribosylation to detect LMM-GBPs in LB. With the first two techniques, we have identified six LMM-GBPs of approximately 27, 25.5, 24.5, 23, 22, and 21 kD that are enriched in a highly purified LB fraction compared with type 2 pneumocyte homogenate, crude membranes, and cytosol. Further characterization of the LB LMM-GBPs by immunoblotting revealed that ras p21 is greatly enriched in the LB fraction compared with other type 2 pneumocyte fractions. In addition, botulinum exoenzyme C3 catalyzed the ADP ribosylation of 20- to 21-kD proteins that were similarly enriched in the LB fraction. In contrast, a monospecific antibody to ADP-ribosylation factor reacted with a 19-kD protein only in the type 2 pneumocyte homogenate and cytosol fractions. Monospecific antibodies to yeast Sec4 protein and to rab 3A did not react with any type 2 pneumocyte proteins. The LMM-GBPs specifically associated with LB may participate in intracellular events required for surfactant packaging and secretion.

Adenosine Diphosphate Ribose↗

PubMedDate not supplied

Immortalization by truncated myc or ras genes and synergism between myc and ras genes in cell transformation.

Human c-myc and normal or mutant T24 H-ras1 genes either linked to the regulatory sequences of the human metallothionein IIa gene or unlinked have been employed individually or in combination to transfect early passage Chinese hamster lung cells. Since the c-myc and H-ras1 genes are present in recombinant plasmids carrying the aminoglycoside phosphotransferase (aph), gene transfectants were selected in the presence of geneticin. A synergistic effect has been observed between myc and H-ras1 genes in measurement of both the number of geneticin resistant colonies obtained and the parameters of morphological transformation and anchorage independence. Out study also demonstrates the ability of truncated myc and ras genes to induce immortalization of hamster cells.

Animals↗

PubMed1997