Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) gene, has two alternate isoforms which are generated by alternative splicing of two exons. One of these isoforms containing exon 48a is expressed at highest levels in muscle. Since neurofibromin is a p21-ras regulator and has been recently shown to be modulated during Schwann cell differentiation, we examined the expression of the NF1 gene product during in vitro muscle differentiation. Previous work demonstrated that C2C12 murine myoblast cell differentiation could be blocked by the introduction of an activated p21-ras protein. Using this model system, we demonstrate that differentiating C2C12 cells upregulate the expression of NF1 mRNA by 2 days of serum starvation concomitant with increased expression of nicotinic acetylcholine receptor mRNA. This upregulation of mRNA expression paralleled an increase in neurofibromin and N-ras levels, but no change in the relative abundance of the isoforms containing exon 23a or exon 48a was observed during in vitro myoblast differentiation. The increase in neurofibromin levels paralleled a decrease in the levels of activated p21-ras as assayed by in vivo 32P-orthophosphate incorporation into p21-ras. These results suggest that in vitro C2C12 cell differentiation is associated with a concomitant increase in NF1 gene expression and decrease in the proportion of activated p21-ras.
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PMID:Modulation of neurofibromatosis type 1 gene expression during in vitro myoblast differentiation. 817 61

We have isolated by subtractive hybridization a novel gene, called H-rev107, which is specifically expressed in a phenotypic revertant of H-ras transformed 208F rat fibroblasts. Apart from oncogene revertants, strong expression of H-rev107 was found in REF52 and EK-3 cells, two fibroblast lines resistant to transformation by activated H-ras oncogenes. In contrast, transformation-sensitive fibroblasts like 208F or NIH3T3 cells expressed only very little H-rev107 RNA. In H-ras or v-src transformed fibroblasts, H-rev107 RNA was undetectable. Introduction of the adenovirus E1A nuclear oncogene into ras-resistant REF52 cells abolished their transformation resistance and repressed the H-rev107 gene. H-rev107 encodes a protein with a molecular weight of 18 kDa without any structural similarity to known proteins. p18H-rev107 exists in two forms which can be distinguished by their electrophoretic mobility; one is localized predominantly in cell membranes, the other in the cytoplasm. In confluent contact-inhibited 208F cells, p18H-rev107 accumulated in cell membranes, while growth arrest induced by serum starvation did not induce H-rev107. In REF52, cell density had no influence on the expression or localization of p18H-rev107. Repression of the H-rev107 gene may be closely associated with the loss of density-dependent growth inhibition and with the expression of the neoplastic phenotype.
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PMID:Subtraction cloning of H-rev107, a gene specifically expressed in H-ras resistant fibroblasts. 829 Feb 59

Biosynthesis of several rat liver proteins is enhanced by amino acid deprivation of cultured hepatocytes or hepatoma cells. One of these proteins, MP-73, was synthesized at a rate 2- to 3-fold greater when cells were incubated for 3-9 h under conditions of amino acid deprivation versus amino acid supplementation. Immunoblotting with polyclonal antibodies prepared against MP-73 localized it to the inner mitochondrial membrane. MP-73 appears to be a hydrophobic, integral membrane protein. MP-73 antibody was used to identify a partial cDNA (NS3.2) of approximately 2 kb. A probe prepared from pNS3.2 identified a transcript in rat Fao hepatoma cells of approximately 4.4 kb that was increased in abundance by more than 20-fold following amino acid starvation of the cells.
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PMID:Enhanced mRNA content in response to amino acid starvation for a 73 kDa protein of the inner mitochondrial membrane. 832 32

The role of Ca2+ and Zn2+ in the initiation of DNA synthesis in NIH 3T3 fibroblasts and c-Ha-ras(val-12) oncoprotein-expressing (NIH 3T3) cells has been studied. Entrapment of the Ca2+ chelator, BAPTA (30 microM), into the cells totally blocked a serum-induced rise in cytosolic free Ca2+ ([Ca2+]i) as determined with fura-2. Serum starvation for 24 h considerably reduced DNA synthesis in control NIH 3T3 fibroblasts. BAPTA treatment reduced serum-induced DNA synthesis and totally inhibited platelet-derived growth factor-induced DNA synthesis in these cells. DNA synthesis of the c-Ha-ras(val-12)-expressing fibroblasts was little affected by serum starvation and unaffected by entrapment of BAPTA into the cells. Intracellular Zn2+ was measured using the fluorescent probe TSQ in intact cells. As determined using image analysis the TSQ fluorescence was distributed throughout the cytoplasm and concentrated around the nucleus. The permeable Zn2+ chelator, TPEN, at a concentration of 10 microM, caused a maximal reduction in TSQ-available Zn2+. This concentration of TPEN totally blocked DNA synthesis both in control and c-Ha-ras(val-12)-expressing fibroblasts. Upon addition of 11 microM Zn2+ DNA synthesis was restored even after TPEN addition. [3H]Thymidine incorporation itself was also sensitive to TPEN treatment. The results suggest that c-Ha-ras(val-12)-induced proliferation is independent of changes in [Ca2+]i. A specific role of Zn2+ in c-Ha-ras-induced proliferation is unlikely since ras-expressing and control cells reacted similarly to Zn2+ deprivation. There seems to be a constant requirement for the presence of Zn2+ in cell proliferation.
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PMID:Ca2+ and Zn2+ dependence of DNA synthesis in untransformed and in Ha-ras(val-12)-expressing NIH 3T3 cells. 835 24

Transformed A5 mouse lung cells were examined for mechanisms that may explain their loss of glucocorticoid-induced growth inhibition. These cells were compared to nontransformed C10 mouse lung cells, which retain this response. Southern blot analysis revealed no major differences in the amount or pattern of restriction fragments for the glucocorticoid receptor (GR) gene between the responsive and nonresponsive cells. Northern blot analysis demonstrated that both cell lines expressed GR mRNA at similar levels and that these mRNAs had similar relative stabilities. The mRNA from both cell lines was used for reverse transcription-polymerase chain reaction amplification and direct sequencing with primers for different regions of the GR cDNA. A conservative mutation previously shown not to affect receptor function was detected within the DNA-binding domain region of the GR from both cell lines. Because of the ability of the transcription factors for activator protein-1 to antagonize GR function, c-jun and c-fos mRNA levels were examined. A5 cells were found to have higher levels of c-jun mRNA than C10 cells both during active cell growth and after serum starvation. Stable transfection of the nonresponsive A5 cells with a rat GR expression vector (A5GR7) resulted in strong glucocorticoid-induced growth inhibition, demonstrating that these cells retain the ability to be growth inhibited by these steroids. The A5GR7 transfectants also had higher mouse mammary tumor virus (MMTV)-chloramphenicol acetyltransferase (CAT) activity than the parental A5 cells and lower levels of c-jun during active cell growth. Transient transfection of the C10 cells with c-jun expression vector strongly reduced glucocorticoid-inducible MMTV-CAT activity. These results suggest that the transformed A5 cells apparently contain functional GR but that the high level of c-jun mRNA expression (probably resulting from the activated Ki-ras allele in these cells) may antagonize their ability to respond to the growth-inhibitory signaling of glucocorticoids.
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PMID:Loss of glucocorticoid-dependent growth inhibition in transformed mouse lung cells. 878 64

The social amoeba Dictyostelium discoideum expresses five ras genes at different stages of development. One of them, DdrasD is expressed during postaggregative development and transcription is induced by extracellular cAMP. A homologue of DdrasD, the DdrasG gene, is expressed exclusively during vegetative growth. We cloned two ras homologues Dmras1 and Dmras2 from the primitive species D. minutum, which show high homology to DdrasD and DdrasG and less homology to the other Ddras genes. In contrast to the DdrasD and DdrasG genes, both the Dmras1 and Dmras2 genes are expressed during the entire course of development. The expression levels are low during growth, increase at the onset of starvation and do not decrease until fruiting bodies have formed. Expression of neither Dmras1 or Dmras2 is regulated by cAMP. So even though the high degree of homology between the ras genes of different species suggests conservation of function, this function is apparently not associated with a specific developmental stage.
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PMID:Two ras genes in Dictyostelium minutum show high sequence homology, but different developmental regulation from Dictyostelium discoideum rasD and rasG genes. 907 71

We recently identified a novel myristylated protein kinase C (PKC) substrate, named SSeCKS (pronounced essex), whose transcription is suppressed > 15 fold in src- or ras-transformed rodent fibroblasts, but not in raf-transformed cells [1, 2]. SSeCKS associates with and controls the elaboration of a cortical cytoskeletal matrix in response to phorbol esters [2], and overexpression of SSeCKS causes growth arrest of untransformed NIH3T3 cells [3]. Our preliminary data suggested that SSeCKS functions as a negative mitogenic regulator by controlling cytoskeletal architecture and that serine phosphorylation of SSeCKS by kinases such as PKC alters its interaction with cytoskeletal matrices and its ability to control mitogenesis. Here, we determine the effects of culture confluency, growth arrest and serum response on the steady-state abundance of SSeCKS RNA and protein and on the relative level of phosphoserine-free SSeCKS. SSeCKS transcription is initially induced by serum factors and by contact-inhibited growth rather than by cell-cycle arrest induced by serum starvation, hydroxyurea or nocodazole, and following serum-induced G1/S progression, SSeCKS transcription is suppressed. SSeCKS protein is hyperphosphorylated on serine residues during G1/S progression but not during the G2/M phase. Finally, we show that the induction of SSeCKS protein expression by contact inhibition is independent of SSeCKS' serum responsiveness. These data suggest that SSeCKS expression and function can be controlled at either the transcriptional or post-translational level in response to serum factors and culture confluency. The data strengthen the notion that SSeCKS plays an important, yet transient, role in cell cycle progression from G0 to G1 that differs from its role in controlling contact-inhibited growth.
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PMID:Cell-cycle regulated expression and serine phosphorylation of the myristylated protein kinase C substrate, SSeCKS: correlation with culture confluency, cell cycle phase and serum response. 935 56

The purpose of this paper was to clarify critical aspects of the behavior of signal transduction activity in normal and cancer cells. 1. Signal transduction activity in the conversion of phosphatidylinositol through PI and PIP kinases and PLC to IP3 is regulated at multiple sites. In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess. 2. The steady-state signal transduction activity as measured by the three enzyme activities and IP3 concentration was markedly up-regulated in rat hepatomas of different growth rates. The steady-state specific activities of the three signal transduction enzymes were elevated in ovarian carcinomas as compared to normal ovary. Increased enzyme activities were also observed in human breast carcinoma cells as compared to normal human breast parenchymal cells. In breast, ovarian and rat hepatoma cells as they go through lag, log and plateau phases, IP3 concentration in the early lag phase increased 4.5- to 20-fold and PI and PIP kinase activities peaked in mid-log phase. These events returned to baseline levels in the plateau phase. PLC activity did not change. 3. The bone marrow PI and PIP kinase activities in 3-day starvation were decreased to 13% and IP3 concentration was reduced to 24%; at 1-day refeeding they returned to normal. PLC activity changed little. These alterations are in line with the rapid t1/2 degradation rates (12 min) of PI and PIP kinases observed in studies with cycloheximide. By contrast, PLC has a long half-life. 4. The molecular action of tiazofurin entails inhibition of IMP DH activity, decrease in GTP and IP3 concentrations, reduction of ras and myc oncogene expression, and signal transduction enzyme activities. These events are followed by induced differentiation and apoptosis. There are also decreases in enzyme activities which have rapid turnover, including TdR kinase, dTMP synthase, and GPRT. In vitro studies indicated that these events are abrogated by addition of guanine which restores GTP concentrations. Therefore, most or all these events were brought about by the reduced GTP concentration in the tiazofurin target cells. 5. Quercetin and genistein are able to inhibit PI and PIP kinase activities and reduce IP3 concentration in vivo and in tissue culture systems. These flavonoids are also inhibitors of cell proliferation and clonogenic ability in rat hepatoma 3924A and in human OVCAR-5 and MDA-MB-435 cells. Quercetin down-regulated the expression of c-myc and Ki-ras oncogenes and led to induced differentiation and apoptosis in K562 cells. Genistein reduced IP3 concentration in vivo and in the tissue culture system. Genistein is antiproliferative and has cytototoxicity in human carcinoma cells. All three drugs, tiazofurin, quercetin and genistein, act, in part at least, through depression of cellular IP3 concentration although the mechanisms may not be identical. 6. Quercetin and genistein, which attack different targets and different phases of the cell cycle, proved to be synergistic in OVCAR-5 cells. The impact of tiazofurin, genistein and quercetin is of interest because the drugs crucially inhibit the display of the neoplastic program of cells and lead to induced differentiation and apoptosis.
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PMID:Regulation of the signal transduction program by drugs. 938 80

We demonstrate in this paper that the G1 phase specific cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D- and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 specific cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The findings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.
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PMID:Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4. 939 49

We purified from Dictyostelium lysates an 88-kDa protein that bound to a subset of small GTPases, including racE, racC, cdc42Hs, and TC4ran, but did not bind to R-ras or rabB. Cloning of the gene encoding this 88-kDa protein revealed that it contained multiple armadillo-like repeats most closely related to the mammalian GTP exchange factor smgGDS. We named this protein darlin (Dictyostelium armadillo-like protein). Disruption of the gene encoding darlin demonstrated that this protein is not essential for cytokinesis, pinocytosis, phagocytosis, or development. However, the ability of darlin null cells to aggregate in response to starvation is severely affected. When starved under liquid medium, the mutant cells were unable to form aggregation centers and streams, possibly because of a defect in cAMP relay signaling. This defect was not due to an inability of the darlin mutants to activate adenylate cyclase in response to G protein stimulation. These results suggest that the darlin protein is involved in a signaling pathway that may modulate the chemotactic response during early development.
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PMID:Identification of darlin, a Dictyostelium protein with Armadillo-like repeats that binds to small GTPases and is important for the proper aggregation of developing cells. 980 99


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