Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:015151 (p21)
 21,217 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EGF receptors are found on the surface of most cells, usually with high and low binding affinities. To investigate functional relationships between EGF (EGF-like growth factors) and oncogenes we have characterized the expression of the epidermal growth factor receptor (EGFr) in H-Ras, v-Myc, and H-Ras-v-Myc transformed Balb/3T3 cells. H-Ras cells show a marked decrease in the number of EGFr molecules per cell compared to parental cells. v-Myc and H-Ras-v-Myc transformed cells express an intermediate level of receptors. The majority of the EGF receptors on the parental and oncogene transformed cells bind EGF with low affinity and this low affinity receptor is down-regulated by oncogene transformation. v-Myc expression, in the H-Ras-v-Myc transformed cells, abrogates the receptor down-regulation seen with H-Ras transformation. The mechanism of abrogation is not a result of a change in the p21-Ras concentration in the H-Ras-v-Myc transformed cells. In addition, the mitogenic response to EGF was examined. H-Ras and H-Ras-v-Myc transformed cells do not respond to EGF mitogenically. In contrast, EGF stimulates DNA synthesis in parental cells and v-Myc transfected cells; this result suggests that growth promoting signals from the EGF receptor may not be required in H-Ras transformed cells.
Cell Mol Biol 1992 Sep
PMID:EGF receptor activity and mitogenic response of Balb/3T3 cells expressing Ras and Myc oncogenes. EGF receptor activity in oncogene transformed cells. 130 8

smg/rap1A/Krev-1 p21 cDNA is known to inhibit v-Ki-ras p21-induced cell transformation in NIH3T3 cells, but the inhibitory mechanism is not clear at present. In the present study, we examined the effect of smg p21s on the c-fos promoter/enhancer linked to the luciferase reporter gene (c-fos-luciferase). After transfection of c-fos-luciferase into NIH3T3 cells constitutively expressing c-Ki-ras(val-12) p21 or activated c-raf-1 kinase, expression of c-fos-luciferase was much higher than after transfection into control NIH3T3 cells. Addition of platelet-derived growth factor (PDGF), 12-O-tetradecanoyl phorbol 13-acetate (TPA) or dibutyryl cyclic AMP (Bt2cAMP) to the control NIH3T3 cells stimulated c-fos-luciferase expression. Transfection of the smg p21 cDNAs inhibited the activated ras p21-, PDGF- or TPA-stimulated c-fos-luciferase expression, but did not inhibit the activated c-raf-1 kinase- or Bt2cAMP-stimulated reaction. These results indicate that smg p21s inhibit the signal pathways from the PDGF receptor, protein kinase C, and ras p21s to the c-fos promoter/enhancer, but not those from c-raf-1 kinase and cyclic AMP-dependent protein kinase to the c-fos promoter/enhancer.
Oncogene 1992 Sep
PMID:smg/rap1/Krev-1 p21s inhibit the signal pathway to the c-fos promoter/enhancer from c-Ki-ras p21 but not from c-raf-1 kinase in NIH3T3 cells. 132 17

The expression of nucleoside diphosphate kinase (NDK) genes has been implicated as a negative regulator of murine and human tumor metastases and is critical to proper development in Drosophila melanogaster. Molecular mechanisms for the role(s) of NDK in these complex processes have not yet been elucidated, but several reports have suggested that these and many other signal transduction pathways may be activated by NDK acting directly on a regulatory GTP-binding protein(s). To test this hypothesis, we examined the ability of NDK to catalyze the phosphorylation of the GDP bound to the following three members of the superfamily of regulatory GTP-binding proteins: Gt, Ha-ras p21, and ARF. We have found no evidence to support the hypothesis that NDK can directly activate any GTP-binding protein. Rather, evidence is presented which clearly shows that all of the GTP formed upon incubation of GTP-binding proteins with NDK is the result of NDK utilizing free GDP as substrate. The GDP bound to the regulatory proteins is not a substrate for NDK under conditions in which free nucleotides are rapidly and efficiently phosphorylated. The importance of appropriate controls for dissociation of GDP from the regulatory proteins both during the NDK reaction and during the analysis of product is demonstrated. We believe there is currently no experimental evidence to support the hypothesis that NDK can directly activate a regulatory GTP-binding protein.
J Biol Chem 1992 Sep 05
PMID:Regulatory GTP-binding proteins (ADP-ribosylation factor, Gt, and RAS) are not activated directly by nucleoside diphosphate kinase. 132 60

The inter-alpha-inhibitor (I alpha I) and pre-alpha-inhibitor (P alpha I) family is composed of three plasma protease inhibitors, I alpha I, P alpha I, and bikunin, whose chains are encoded by a set of three evolutionarily related heavy (H) chain genes designated H1, H2, and H3 and a fourth gene, the so-called alpha 1-microglobulin/bikunin precursor (AMBP) gene. The latter codes for a precursor that splits into: (i) alpha 1-microglobulin, which belongs to the lipocalin superfamily; and (ii) bikunin, which is made up of two tandemly arranged protease inhibitor domains and belongs to the superfamily of Kunitz-type protease inhibitors. The bikunin chain is found in I alpha I and P alpha I molecules and it is also present as a free molecule in plasma. In human, the AMBP and H2 genes have been mapped to 9q32-q34 and 10p14-p15, respectively, while the H1 and H3 genes are tandemly located at 3p21.1-p21.2. In situ hybridization mappings indicate that the mouse AMBP gene (Intin-4) is located at 4C1----C4, and the H1 (Intin-1) and H3 (Intin-3) genes are colocated at 14A2----C1. In interspecific backcrosses (C57BL/6Pas x Mus spretus) a TaqI restriction variant in (and/or near) the H2 (Intin-2) gene identified a linkage of this gene with other polymorphic loci, which assigns Intin-2 to the centromeric area of chromosome 2. All such assignments are in conserved chromosomal regions between human and mouse. Therefore the genetic events that gave rise to the four I alpha I family genes took place prior to the divergence between human and mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
Genomics 1992 Sep
PMID:Homologous chromosomal locations of the four genes for inter-alpha-inhibitor and pre-alpha-inhibitor family in human and mouse: assignment of the ancestral gene for the lipocalin superfamily. 138 2

The residue Gln61 is assumed to play a major role in the mechanism of ras p21, and mutations of this residue are often found in human tumors. Such mutations lead to a major reduction in the rate of GTP hydrolysis by the complex of ras p21 and the GTPase activating protein (GAP) and lock the protein in a growth-promoting state. This work examines the role of Gln61 in ras p21 by using computer simulation approaches to correlate the structure and energetics of this system. Free energy perturbation calculations and simpler electrostatic considerations demonstrate that Gln61 is unlikely to serve as the general base in the intrinsic GAP-independent reaction of p21. Glutamine is already a very weak base in water, and surprisingly the GlnH+ OH-reaction intermediate is even less stable in the protein active site than in the corresponding reaction in water. The electrostatic field of Glu63, which could in principle stabilize the protonated Gln61, is found to be largely shielded by the surrounding solvent. However, it is still possible that Gln61 is a general base in the GAP/ras p21 complex since this system could enhance the electrostatic effect of Glu63. It is also possible that the gamma-phosphate acts as general base and that Gln61 accelerates the reaction by stabilizing the OH- nucleophile. If such a mechanism is operative, then GAP may enhance the effect of Gln61 by preorienting its hydrogen bonds in the transition-state configuration.
Biochemistry 1992 Sep 22
PMID:On the mechanism of guanosine triphosphate hydrolysis in ras p21 proteins. 139 Jun 53

The ram gene was isolated from rat megakaryocyte cDNA library with an oligonucleotide probe which is specific for a low M(r) GTP-binding proteins c25KG purified from human platelets. Its gene product (ram p25) is a monomeric 25-kDa guanine nucleotide-binding protein. The protein was expressed by using baculovirus transfer vector, pAcYM1, which allowed the production at a high level of soluble recombinant ram p25 in Spodoptera frugiperda (Sf9) cells under the control of polyhedrin promoter. The expressed protein in cytosol of Sf9 cells was purified to near homogeneity by a combination of DEAE-Toyopearl 650(S) and hydroxyapatite HCA-100S column chromatography. The purified ram p25 bound approx. 0.8 +/- 0.02 mol of guanosine 5'-O-1-thiotriphosphate (GTP gamma S)/mol of protein with a Kd value of 340 +/- 4.91 nM in a reaction mixture containing 10 microM of free magnesium ions. In the presence of 5 mM Mg2+, [3H]GDP was dissociated from ram p25 at the rate of 0.015 +/- 0.0010 min-1 and the dissociation was greatly enhanced by addition of 250 mM (NH4)2SO4. The rate of [gamma-32P]GTP-hydrolysis for ram p25 was 0.010 +/- 0.0012 min-1. Thus, it was indicated that the GTP-hydrolysis reaction is a rate-limiting step in the guanine nucleotide turnover of ram p25. ram p25 shares 23 and 80% amino-acid homology with the Ha-ras p21 and c25KG protein, respectively, and is similar to them in GTP gamma S binding activity in a time- and dose-dependent manner. But it differs from ras p21 in the rate-limiting step of the guanine nucleotide turnover.
Biochim Biophys Acta 1992 Sep 23
PMID:Purification and characterization of a low M(r) GTP-binding protein, ram p25, expressed by baculovirus expression system. 139 Sep 22

N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) administration to rats followed by sodium saccharin results in transitional cell carcinomas of the bladder, of which 24% harbor an activated H-ras gene. Since 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) is the mutagenic and carcinogenic metabolite of FANFT in vivo, we wished to examine ras activation in in vitro ANFT-transformed rat bladder epithelial cells as well as four cell lines established in culture from in vivo FANFT-induced rat bladder tumors. Screening by Western blotting revealed no enhanced levels of p21ras in ANFT-transformed cells nor in cells established in culture from FANFT-induced rat bladder carcinomas. Further investigations using immunohistochemical staining with a different pan-reactive p21 monoclonal antibody (Cetus Corporation) specific for this method, however, showed two groups of cells from FANFT-induced rat bladder tumors had enhanced immunoreactivity. Apart from this, p21ras expression of most of the cells groups varied little from the controls. We examined the reported hot spots (exons 1 and 2) of each of the ras genes (H-, K- and N-ras) by direct sequencing of amplified DNA. No mutations were present. We conclude, therefore, that ANFT transformation of primary rat bladder epithelial cells in vitro may not in this case be mediated by ras activation, although this is difficult to determine since others have observed that optimal culture conditions can select for certain populations of cells without ras activation.
Carcinogenesis 1992 Sep
PMID:Ras involvement in cells transformed with 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in vitro and with N-[4-(5-nitro-2-furyl)-2-thiazoyl]formamide in vivo. 139 51

We examined the localization of DNA replicating cells and ras oncogene product p21 positive cells in proliferating skin diseases, such as psoriasis vulgaris, lichen planus, verruca vulgaris, verruca plana juvenilis and seborrheic keratosis. ras p21-positive cells were found rather in the differentiated layers than in the proliferating layers of the epidermis. We indicate that the expression of ras p21 can be associated with the differentiation of epidermal keratinocytes not only in tumor tissues but also in inflammatory skin disease.
J Dermatol Sci 1992 Sep
PMID:Association of ras p21 with differentiation of epidermal keratinocytes in proliferating skin diseases. 141 83

RAS protein (p21 ras) requires farnesyl (an intermediate of cholesterol synthesis) for activation. Activating mutations of K-ras gene have been detected in most human pancreatic adenocarcinomas. In the present study, the effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, the rate-limiting enzyme of cholesterol synthesis, on the growth of five pancreatic cancer cell lines (human-CAV, MIA Paca2, CAPAN2 and PANC1, and hamster-H2T) in vitro and of two cell lines (CAV and H2T) in vivo was examined. Inhibition of cell growth was observed with lovastatin doses at or above 2.5 micrograms/mL for H2T, CAV, MIA Paca2, and CAPAN2 or 10 micrograms/mL in PANC1. The H2T cell line was studied further to determine the reversibility of growth inhibition. Mevalonic acid (1 mmol/L) reversed lovastatin-induced inhibition of cell growth if it was added with lovastatin (2.5 micrograms/mL). Similarly, removal of lovastatin from the medium within 24 hours after treatment allowed recovery of cell growth. The effect of lovastatin on cell growth was irreversible after 48 hours of exposure. The survival fraction of H2T cells was markedly decreased by 1- or 24-hour exposure to 75 micrograms/mL but not to doses ranging from 0.5 to 60 micrograms/mL of lovastatin. Growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice was inhibited by a subcutaneous infusion of lovastatin (50 micrograms/h). These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for growth of pancreatic cancer cells and suggest that lovastatin should be further examined as a potential therapeutic agent for pancreatic cancer.
Gastroenterology 1992 Sep
PMID:Inhibition of pancreatic adenocarcinoma cell growth by lovastatin. 149 46

The hepatitis B virus capsid or core protein (p21.5) binds nucleic acid through a carboxy-terminal protamine region that contains nucleic acid-binding motifs organized into four repeats (I to IV). Using carboxy-terminally truncated proteins expressed in Escherichia coli, we detected both RNA- and DNA-binding activities within the repeats. RNA-binding and packaging activity, assessed by resolving purified E. coli capsids on agarose gels and disclosing their RNA content with ethidium bromide, required only the proximal repeat I (RRRDRGRS). Strikingly, a mutant in which four Arg residues replaced repeat I was competent to package RNA, demonstrating that Arg residues drive RNA binding. In contrast, probing immobilized core proteins with 32P-nucleic acid revealed an activity which (i) required more of the protamine region (repeats I and II), (ii) appeared to bind DNA better than RNA, and (iii) was apparently modulated by phosphorylation in p21.5 derived from Xenopus oocytes. Deletion analysis suggested that this activity may depend on an SPXX-type DNA-binding motif in repeat II. Similar motifs found in repeats III and IV may also function to bind DNA. On the basis of these observations, together with a reinterpretation of recent studies showing that capsid protein mutants cause defects in viral genome replication, we propose a model suggesting that hepadnavirus capsid proteins participate directly in the intracapsid reverse transcription of RNA into DNA. In this model, repeat I binds RNA whereas the distal repeats are progressively recruited to bind elongating DNA strands. The latter motifs may be required for replication to be energetically feasible.
J Virol 1992 Sep
PMID:RNA- and DNA-binding activities in hepatitis B virus capsid protein: a model for their roles in viral replication. 150 Dec 73


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