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Gene Review

HRAS  -  Harvey rat sarcoma viral oncogene homolog

Homo sapiens

Synonyms: C-BAS/HAS, C-H-RAS, C-HA-RAS1, CTLO, GTPase HRas, ...
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Disease relevance of HRAS


Psychiatry related information on HRAS


High impact information on HRAS


Chemical compound and disease context of HRAS


Biological context of HRAS

  • Specifically, we found that oncogenic forms of HRAS (HRAS(G12V)) but not its downstream target BRAF (BRAF(V600E)), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER [1].
  • Met dependency is acquired simultaneously with cell transformation, as observed with HBL 100, a human mammary epithelial cell line that acquired increased malignancy as a function of in vitro passage number, and NIH/3T3 (J10), a mouse fibroblast line transformed by transfection with the human HRAS oncogene [19].
  • An experimental approach was developed to identify and isolate a human gene capable of suppressing the transforming activity of the HRAS oncogene in FE-8 cells [20].
  • By use of probes that recognize six genes of human 11p (INS, CAT, HBBC, CALC, PTH, and HRAS), the corresponding genes were localized by in situ hybridization on Chinese hamster chromosome 3 [21].
  • The transformed phenotype of rat FE-8 cells transfected by an activated human HRAS gene was suppressed upon fusion with normal cells [20].

Anatomical context of HRAS


Associations of HRAS with chemical compounds

  • Further examination of the role of poly(L-lysine) in potentiating tyrosine phosphorylation of the HRAS protein and calmodulin by purified insulin receptor kinase indicates that poly(L-lysine) affects the conformation of these protein substrates as well as that of the receptor kinase domain [26].
  • HRAS-transformed FE-8 cells showed an increased sensitivity toward ouabain when compared to their normal counterparts [20].
  • The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS [27].
  • The GTP binding regions of p21 ras and a C-terminal cysteine involved in membrane anchoring are also present in ral; this strongly suggests that ral is a GTP binding protein with membrane localization [28].
  • We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT) [29].

Physical interactions of HRAS


Enzymatic interactions of HRAS

  • We then determined whether the KRAS basic domain peptide plays a role similar to that of poly(L-lysine) and found that both the HRAS protein and calmodulin are phosphorylated by the receptor kinase in the presence of the KRAS basic domain peptide [26].
  • The result of Western blotting analysis confirmed that Ets1 was really phosphorylated when mutant K-ras was activated [35].
  • Finally, we also show that a 62-kD protein coimmunoprecipitating with the p21ras GTPase activating protein (GAP) is heavily tyrosine phosphorylated only after CD2 stimulation [36].

Co-localisations of HRAS


Regulatory relationships of HRAS

  • These results suggest a novel mechanism whereby type I IFNs interrupt IL-6-promoted mitogenesis of myeloma cells in part by preventing the formation of essential signaling complexes leading to p21ras activation [38].
  • This mechanism also may be relevant under normal conditions. p53 also is capable of inhibiting transforming p21ras [39].
  • These oncogenes, which are frequently expressed in human malignancies, code for proteins (p21ras) that are locked in the activated GTP-bound state because their GTPase is refractory to the ras-specific GTPase activating protein (GAP) [39].
  • We conclude that Raf-1 is expressed in its active form in human pancreatic cancer regardless of K-ras status [40].
  • Subsequent analysis of full-length RIN1 clones showed that the protein product of this gene is a downstream effector of RAS and binds with high affinity and specificity to activated HRAS [41].

Other interactions of HRAS

  • Two substrates for TCR-regulated protein tyrosine kinases (PTKs) have been implicated in p21ras activation in T cells: p95vav and a 36-kD protein that associates with a complex of Grb2 and the Ras exchange protein Sos [42].
  • These studies show that for CD28 signaling, the activation of p21ras correlates more closely with p36 tyrosine phosphorylation than with Vav tyrosine phosphorylation [42].
  • MGMT methylation was associated with G-to-A mutation in K-ras (P = 0.006), and hMLH1 methylation was associated with MSI-high (P = 0.01) [43].
  • In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes [44].
  • We have investigated the in vitro tyrosine phosphorylation of the HRAS and KRAS proteins by human placental insulin receptor kinase [26].

Analytical, diagnostic and therapeutic context of HRAS

  • Direct sequence analysis of the amplified DNA indicated equal presence of a wild-type (GGC) and mutant (GTC) allele of the HRAS gene [22].
  • Efforts to reconstruct multistep tumorigenesis in cell culture have shown that two types of oncogenes (typified by HRAS and MYC) can cooperate to elicit complete transformation [45].
  • Examination of frozen cross sections by in situ hybridization revealed that focal areas of the tumor produced by the MMS-SCC-83-01-82 cells expressed MYC and HRAS mRNA [14].
  • Polymerase chain reaction (PCR) amplified the K-, N-, and HRAS 12, 13, and 61 codons of these specimens, and mutations were detected with mutation-specific oligonucleotide probe hybridization of Southern and slot blots [46].
  • The expression of normal and mutant ras genes in human acute leukemias was assessed by the direct analysis of p21ras polypeptides, using immunoprecipitation with monoclonal antibodies [47].


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  2. Activated protooncogenes in human lung tumors from smokers. Reynolds, S.H., Anna, C.K., Brown, K.C., Wiest, J.S., Beattie, E.J., Pero, R.W., Iglehart, J.D., Anderson, M.W. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  3. Malignant transformation of human fibroblasts caused by expression of a transfected T24 HRAS oncogene. Hurlin, P.J., Maher, V.M., McCormick, J.J. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  4. Suppression of tumor growth by senescence in virally transformed human fibroblasts. O'Brien, W., Stenman, G., Sager, R. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  5. Inherited breast and ovarian cancer. Szabo, C.I., King, M.C. Hum. Mol. Genet. (1995) [Pubmed]
  6. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. Nat. Genet. (2005) [Pubmed]
  7. A dyslexia susceptibility locus (DYX7) linked to dopamine D4 receptor (DRD4) region on chromosome 11p15.5. Hsiung, G.Y., Kaplan, B.J., Petryshen, T.L., Lu, S., Field, L.L. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  8. Induction of p21ras in Alzheimer pathology. Gärtner, U., Holzer, M., Heumann, R., Arendt, T. Neuroreport (1995) [Pubmed]
  9. Molecular epidemiology of pancreatic cancer. Li, D. Cancer journal (Sudbury, Mass.) (2001) [Pubmed]
  10. Does detection of K-ras mutations in pancreatic juice influence clinical decision making? O'Mahony, S., Sreedharan, A. European journal of gastroenterology & hepatology. (2001) [Pubmed]
  11. Signal transduction by the B cell antigen receptor and its coreceptors. Cambier, J.C., Pleiman, C.M., Clark, M.R. Annu. Rev. Immunol. (1994) [Pubmed]
  12. A genome-wide survey of RAS transformation targets. Zuber, J., Tchernitsa, O.I., Hinzmann, B., Schmitz, A.C., Grips, M., Hellriegel, M., Sers, C., Rosenthal, A., Schäfer, R. Nat. Genet. (2000) [Pubmed]
  13. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Morales, C.P., Holt, S.E., Ouellette, M., Kaur, K.J., Yan, Y., Wilson, K.S., White, M.A., Wright, W.E., Shay, J.W. Nat. Genet. (1999) [Pubmed]
  14. Nontumorigenic squamous cell carcinoma line converted to tumorigenicity with methyl methanesulfonate without activation of HRAS or MYC. Milo, G.E., Shuler, C., Kurian, P., French, B.T., Mannix, D.G., Noyes, I., Hollering, J., Sital, N., Schuller, D., Trewyn, R.W. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  15. NF-{kappa}B inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells. Kwon, O., Kim, K.A., Kim, S.O., Ha, R., Oh, W.K., Kim, M.S., Kim, H.S., Kim, G.D., Kim, J.W., Jung, M., Kim, C.H., Ahn, J.S., Kim, B.Y. Carcinogenesis (2006) [Pubmed]
  16. Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumour cells. Di Paolo, A., Danesi, R., Nardini, D., Bocci, G., Innocenti, F., Fogli, S., Barachini, S., Marchetti, A., Bevilacqua, G., Del Tacca, M. Br. J. Cancer (2000) [Pubmed]
  17. Ras oncogenes and p53 tumor suppressor gene analysis in cardiac myxomas. Karga, H., Papaioannou, P., Karayianni, M., Papadimitriou, K., Priftis, D., Voujuklakis, T., Migdou, B., Nanas, J., Papapetrou, P. Pathol. Res. Pract. (2000) [Pubmed]
  18. The sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 ('Iressa') is not related to the expression of EGFR or HER-2 or to K-ras gene status. Suzuki, T., Nakagawa, T., Endo, H., Mitsudomi, T., Masuda, A., Yatabe, Y., Sugiura, T., Takahashi, T., Hida, T. Lung Cancer (2003) [Pubmed]
  19. Methionine dependency of malignant tumors: a possible approach for therapy. Breillout, F., Antoine, E., Poupon, M.F. J. Natl. Cancer Inst. (1990) [Pubmed]
  20. Partial reversion of the transformed phenotype in HRAS-transfected tumorigenic cells by transfer of a human gene. Schaefer, R., Iyer, J., Iten, E., Nirkko, A.C. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  21. Genetic analysis of tumorigenesis: a conserved region in the human and Chinese hamster genomes contains genetically identified tumor-suppressor genes. Stenman, G., Sager, R. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  22. Characterization of mutagen-activated cellular oncogenes that confer anchorage independence to human fibroblasts and tumorigenicity to NIH 3T3 cells: sequence analysis of an enzymatically amplified mutant HRAS allele. Stevens, C.W., Manoharan, T.H., Fahl, W.E. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  23. Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells. Stearns, M., Tran, J., Francis, M.K., Zhang, H., Sell, C. Cancer Res. (2005) [Pubmed]
  24. High p21RAS expression levels correlate with chromosome 8 rearrangements in benign human mixed salivary gland tumors. Stenman, G., Sandros, J., Mark, J., Nordkvist, A. Genes Chromosomes Cancer (1989) [Pubmed]
  25. Exclusion of linkage between hypokalemic periodic paralysis (HOKPP) and three candidate loci. Casley, W.L., Allon, M., Cousin, H.K., Ting, S.S., Crackower, M.A., Hashimoto, L., Cornélis, F., Beckmann, J.S., Hudson, A.J., Ebers, G.C. Genomics (1992) [Pubmed]
  26. In vitro tyrosine phosphorylation studies on RAS proteins and calmodulin suggest that polylysine-like basic peptides or domains may be involved in interactions between insulin receptor kinase and its substrate. Fujita-Yamaguchi, Y., Kathuria, S., Xu, Q.Y., McDonald, J.M., Nakano, H., Kamata, T. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  27. The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS. Gelernter, J., Kennedy, J.L., van Tol, H.H., Civelli, O., Kidd, K.K. Genomics (1992) [Pubmed]
  28. The ral gene: a new ras related gene isolated by the use of a synthetic probe. Chardin, P., Tavitian, A. EMBO J. (1986) [Pubmed]
  29. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Lipton, L., Halford, S.E., Johnson, V., Novelli, M.R., Jones, A., Cummings, C., Barclay, E., Sieber, O., Sadat, A., Bisgaard, M.L., Hodgson, S.V., Aaltonen, L.A., Thomas, H.J., Tomlinson, I.P. Cancer Res. (2003) [Pubmed]
  30. Quantitative analysis of the complex between p21ras and the Ras-binding domain of the human Raf-1 protein kinase. Herrmann, C., Martin, G.A., Wittinghofer, A. J. Biol. Chem. (1995) [Pubmed]
  31. p21ras couples the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes. Izquierdo, M., Leevers, S.J., Marshall, C.J., Cantrell, D. J. Exp. Med. (1993) [Pubmed]
  32. A mutant insulin receptor induces formation of a Shc-growth factor receptor bound protein 2 (Grb2) complex and p21ras-GTP without detectable interaction of insulin receptor substrate 1 (IRS1) with Grb2. Evidence for IRS1-independent p21ras-GTP formation. Ouwens, D.M., van der Zon, G.C., Pronk, G.J., Bos, J.L., Möller, W., Cheatham, B., Kahn, C.R., Maassen, J.A. J. Biol. Chem. (1994) [Pubmed]
  33. Ras oncogene transformation of human B lymphoblasts is associated with lymphocyte activation and with a block of differentiation. Sirinian, M.I., Marchetti, A., Di Rocco, G., Starace, G., Jucker, R., Nasi, S. Oncogene (1993) [Pubmed]
  34. VEGF stimulates MAPK through a pathway that is unique for receptor tyrosine kinases. Doanes, A.M., Hegland, D.D., Sethi, R., Kovesdi, I., Bruder, J.T., Finkel, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  35. Ets1 was significantly activated by ERK1/2 in mutant K-ras stably transfected human adrenocortical cells. Chen, Y.F., Shin, S.J., Lin, S.R. DNA Cell Biol. (2005) [Pubmed]
  36. Tyrosine phosphorylation and association with phospholipase C gamma-1 of the GAP-associated 62-kD protein after CD2 stimulation of Jurkat T cell. Hubert, P., Debré, P., Boumsell, L., Bismuth, G. J. Exp. Med. (1993) [Pubmed]
  37. Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease is highly co-localized with p21ras and p16INK4a. Lüth, H.J., Holzer, M., Gertz, H.J., Arendt, T. Brain Res. (2000) [Pubmed]
  38. Interferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells. Berger, L.C., Hawley, R.G. Blood (1997) [Pubmed]
  39. Role of GTPases and GTPase regulatory proteins in oncogenesis. Grunicke, H.H., Maly, K. Critical reviews in oncogenesis. (1993) [Pubmed]
  40. Activation of Raf-1 in human pancreatic adenocarcinoma. Berger, D.H., Jardines, L.A., Chang, H., Ruggeri, B. J. Surg. Res. (1997) [Pubmed]
  41. The RIN Family of Ras Effectors. Bliss, J.M., Venkatesh, B., Colicelli, J. Meth. Enzymol. (2005) [Pubmed]
  42. The role of p21ras in CD28 signal transduction: triggering of CD28 with antibodies, but not the ligand B7-1, activates p21ras. Nunès, J.A., Collette, Y., Truneh, A., Olive, D., Cantrell, D.A. J. Exp. Med. (1994) [Pubmed]
  43. Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas. Kim, S.G., Chan, A.O., Wu, T.T., Issa, J.P., Hamilton, S.R., Rashid, A. Gastroenterology (2003) [Pubmed]
  44. Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. Smith, G., Carey, F.A., Beattie, J., Wilkie, M.J., Lightfoot, T.J., Coxhead, J., Garner, R.C., Steele, R.J., Wolf, C.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  45. Oncogene v-src transforms and establishes embryonic rodent fibroblasts but not diploid human fibroblasts. Hjelle, B., Liu, E., Bishop, J.M. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  46. Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization. Moul, J.W., Theune, S.M., Chang, E.H. Genes Chromosomes Cancer (1992) [Pubmed]
  47. Expression of normal and mutant ras proteins in human acute leukemia. Shen, W.P., Aldrich, T.H., Venta-Perez, G., Franza, B.R., Furth, M.E. Oncogene (1987) [Pubmed]
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