Disease relevance of Hras

• Using the whole-cell patch-clamp technique we have investigated the role of endogenous p21-ras in the regulation of VDCCs in primary cultured dorsal root ganglion (DRG) neurons obtained from neonatal rats [1].
• In cooperation with the cellular oncogene Harvey rat sarcoma viral oncogene homolog (Hras), LNA-1 transformed primary rat embryo fibroblasts and rendered them tumorigenic [2].
• The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells [2].
• A normal human gene homologous to the p21 ras oncogene of Harvey murine sarcoma virus induced oncogenic transformation and high p21 ras levels in murine fibroblasts when this gene was ligated to a control element (the long terminal repeat) from a murine or feline retrovirus [3].
• Overexpression of the H-rev107 cDNA in HRAS-transformed ANR4 hepatoma cells or in FE-8 fibroblasts resulted in 75% reduction of colony formation [4].

High impact information on Hras

• Mammalian farnesyltransferase, which attaches a 15 carbon isoprenoid, farnesyl, to a cysteine in p21ras proteins, contains two subunits, alpha and beta [5].
• We report the identification, purification, and characterization of a farnesyl:protein transferase that transfers the farnesyl moiety from farnesyl pyrophosphate to a cysteine in p21ras proteins [6].
• Effective peptides included the COOH-terminal sequences of all known p21ras proteins as well as those of lamin A and B [6].
• Ras (p21ras) interacts directly with the catalytic subunit of phosphatidylinositol-3-OH kinase in a GTP-dependent manner through the Ras effector site [7].
• A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1 [8].

Chemical compound and disease context of Hras

• These results suggest that an agonist for a pertussis toxin-insensitive G protein-coupled receptor may initiate the cross-talk with non-receptor-type tyrosine kinases, thereby activating p21 ras using a similar mechanism as receptor tyrosine kinase-induced p21 ras activation [9].
• 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and mRNA levels were significantly reduced in FRTL-5 cells transformed with the Kirsten-Moloney sarcoma virus (KiMol); these cells have lost thyrotropin dependence and express high levels of p21ras [10].
• c-H-ras and c-K-ras gene hypomethylation in the livers and hepatomas of rats fed methyl-deficient, amino acid-defined diets [11].
• 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 [12].
• These studies demonstrate that a lipid-soluble HMG-CoA reductase inhibitor, lovastatin, may prevent angiotensin II-induced cardiac hypertrophy, at least in part, through p21ras/MAP kinase pathway, which is linked to mevalonate metabolism [13].

Biological context of Hras

• We developed an assay to measure point mutations present in tissues at a frequency of 10(-5) and have now applied this assay to measure the specific G to A transition of the Hras gene in rat mammary epithelium [14].
• G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras [15].
• We have used the inhibitory effect of cAMP to investigate whether phosphorylation of mSos, a p21ras nucleotide exchange factor, is dependent on the activity of the raf-1 kinase/ERK2 pathway [16].
• To do so we selected for study an immortalized, but nontumorigenic line of rat intestinal epithelial cells, called IEC-18, and several tumorigenic variants of IEC-18 obtained by transfection with a mutant (activated) c-H-ras oncogene [17].
• Massive programmed cell death in intestinal epithelial cells induced by three-dimensional growth conditions: suppression by mutant c-H-ras oncogene expression [17].

Anatomical context of Hras

• Expression of Krev-1 and c-H-ras proto-oncogenes in the rat spinal cord and the effects of noxious stimulation [18].
• Therefore, we investigated the role of pp60c-src and p21ras in rat aortic smooth muscle cell proliferation induced by several G protein-coupled receptors [15].
• This function is reportedly mediated in part by inhibition of B cell antigen receptor (BCR)-mediated p21ras activation, though the basis of this inhibition is unknown [19].
• We measured the responses elicited after x irradiation of cells from the normal rat cell line REF52 as well as two oncogene-transformed REF52 cell lines with E1a or E1a plus the mutated c-Harvey-ras T24 (HRAS1 T24) allele [20].
• We show here that stimulation of the G q protein-coupled angiotensin II (Ang II) receptor causes activation of p21 ras in cardiac myocytes [9].

Associations of Hras with chemical compounds

• GGA to GAA mutations in the 12th codon of the Hras gene are frequently observed in rat mammary tumors induced by N-nitroso-N-methylurea (NMU) [14].
• Growth factor receptor binding protein-2 (GRB2) and Shc have been shown to link growth factor receptor activation with guanine nucleotide exchange on p21-ras [21].
• Various signalling proteins, including nerve growth factor (NGF), p21-ras and src tyrosine kinases, have been suggested to have a role in the regulation of neuronal VDCCs [1].
• The heterotrimeric G q protein-coupled angiotensin II receptor activates p21 ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes [9].
• The first peak of activation of p21ras, at 2-5 min, is mediated by immediate association of phosphorylated Shc with the guanosine exchange factor Sos1 via the adaptor protein Grb2 [22].

Physical interactions of Hras

• The connection of the EGFR to p21ras activation can occur through binding of Grb2.Sos complexes to the EGFR or through the adaptor protein Shc via EGFR.Shc.Grb2.Sos multimeric complexes [23].
• We have previously reported that immobilized p21ras forms a GMPPNP-dependent complex with a MEK activity [24].
• HMG-CoA reductase inhibitors are known to modulate some cellular signal transduction systems by blocking the membrane attachment of low molecular weight GTP binding proteins such as p21ras [25].
• It is concluded that in hepatocytes (a) the majority of p21ras is bound to the plasma membrane and (b) p21ras is not directly involved in the activation by GTP[S] of phospholipase D [26].

Regulatory relationships of Hras

• Src tyrosine kinases have been suggested to activate p21-ras [1].
• Our data provide evidence that ET-1-induced biphasic p21ras activation causes sequential stimulation of divergent downstream signaling pathways [22].
• The mitogen-activated protein kinase cascade is activated by B-Raf in response to nerve growth factor through interaction with p21ras [27].
• Here we show that in Rat-1 fibroblasts, cAMP-raising agents inhibit p21ras-mediated mitogen-activated protein (MAP) kinase activation induced by either epidermal growth factor or lysophosphatidic acid [28].
• IL-1 beta-induced class II upregulation shows moderate signs of p21ras or/and PKC dependency, whereas IL-1 alpha strongly activates both pathways that probably regulate different functions [29].

Other interactions of Hras

• This effect appears largely to involve NGF receptor tyrosine kinase activation of p21-ras [1].
• Biphasic activation of p21ras by endothelin-1 sequentially activates the ERK cascade and phosphatidylinositol 3-kinase [22].
• Ang II causes rapid tyrosine phosphorylation of Shc and its association with Grb2 and mSos-1, a guanine nucleotide exchange factor of p21 ras [9].
• Mitogen-activated protein (MAP) kinases Raf-1, pp60src, and p21ras all play important roles in the transfer of signals from the cell surface to the nucleus [30].
• The signaling pathway coupling epidermal growth factor receptors to activation of p21ras [23].

Analytical, diagnostic and therapeutic context of Hras

• Deprivation of NGF combined with microinjection of p21-ras antibody (Y13-259), however, caused an even greater reduction of I(max) [1].
• In an effort to identify proteins interacting with p21ras, we have used in vivo crosslinking techniques on Rat-1 fibroblasts and derived cell lines overexpressing p21ras and immunoprecipitation with polyclonal anti-p21ras antibodies [31].
• Mutations in p21ras were analyzed using an enzyme-linked immunosorbent assay [32].
• To address this issue, we identified genes suppressed in HRAS-transformed rat fibroblasts but upregulated after treatment with the demethylating agent 5-Aza-2-deoxycytidine and with the MEK1,2 inhibitor U0126 [33].
• The proto-oncogene c-H-ras is considered to be a key transducer in various growth-signaling events [34].

References