RAS family

Franz Watzinger, Thomas Lion

March 1999

(Children Cancer Reserch Institute, St. Anna Children's Hospital, A-1090 Vienna, AUSTRIA)

DNA/RNA

The establishment of an in vitro assay to screen for active transformation ofmouse NIH 3T3 fibroblasts has revealed transforming genes identified as humanhomologs of Harvey or Kirsten murine sarcoma virus oncogenes (v-Ha-ras, or v-Ki-ras,respectively). Thereupon, an additional transforming gene was found in human neuroblastomaand fibrosarcoma cell lines that has been identified as the third functional memberof the ras gene family. This gene have been termed N-ras. Thus, the human rasfamily consists of three proto-oncogenes, c-Harvey(H)-ras, c-Kirsten (K)-ras, and N-ras,no c-prefix was added because no viral counterpart was found. Additionally, geneswere found in the genome of human and other mammalian species that display highhomology to the functional ras genes but lack intervening sequences (introns).These genes were identified as processed and inactivated pseudogenes. Functionalras genes differ greatly in length due to large differences in the size of theirintrons ranging from about 6kb to 50kb, but they each have 4 coding exons. Thehuman K-ras gene contain an alternative fourth coding exon. Alternative RNA splicingspecifies either of two isomorphic proteins differing by 25 amino acid residuesat their carboxy-terminus. Ras genes are expressed in all tissues, have a promotorregion with multiple GC boxes, but lack a TATA- or CCAT-box; features resemblingthe promotors of housekeeping genes (Lowndes et al., 1999).
A comparison of human H-, K-, and N-ras nucleotide sequences with the correspondingregions in other mammalian species reveals a remarkable sequence similarity (Watzingeret al., 1998). All differences are synonymous changes with no effect on the aminoacid sequence of RAS proteins, indicating a strong evolutionary pressure on theamino acid sequence of these genes.
The ras oncogenes in various human tumors harbor point mutations that confer transformingactivity. Mutations leading to an amino acid substitution at the positions 12,13, and 61 are the most common in naturally occurring (i.e. non-experimental)(Kiaris and Spandidos, 1999) neoplasms and experimentally induced animal tumors(Mangues and Pellicer, 1992; Stanley, 1995) (see following sections).
In addition to the most frequent mechanism of point-mutational activation, overexpressionof non-mutated ras genes can also convert normal ras genes into oncogenes. Theincreased amount of the corresponding mRNA derives either from high transcriptionalactivity of heterologous promotors and enhancers (Chakraborty et al., 1991) orresults from amplified ras genes located either intrachromosomally as homogeneouslystaining regions or extrachromosomally as double minute chromosomes (Nishimuraand Sekiya, 1987).

Functional aspects of RAS proteins

Mammalian ras genes code for closely related, small proteins of 189 amino acids witha molecular weight of 21,000 Daltons (p21). When the alternative exon of H- or K-rasis used, proteins of 170 or 188 amino acids are synthesized. The molecular weightof the H-ras protein variant is 19,000 Daltons and that of the K-ras variant is notdistinguishablefrom the normal RAS proteins.
RAS proteins are localized in the inner plasma membrane, bind GDP and GTP andpossess an intrinsic GTPase activity, implicated in the regulation of their activity.Because of the functional resemblance to G-Proteins, p21RAS have been hypothesizedto be also involved in different types of ligand-mediated signal transductionpathways. Later, RAS proteins were shown to influence proliferation, differentiation,transformation, and apoptosis by relaying mitogenic and growth signals into thecytoplasm and the nucleolus (Khosravi Far and Der, 1994). In a normal cell mostof the RAS molecules are present in an inactive GDP-bound conformation. An extracellularstimulus initiates the release of GDP and the subsequent binding of GTP. Thisconformational change enables the interaction with the putative effector moleculesand permits the transmission of signals. Finally, the active GTP-bound state isturned off by hydrolysis of GTP to GDP and inorganic phosphate.
The intrinsic GTPase activity is rather weak, not sufficiently effective for signaltransduction pathways where rapid inactivation is required. In order to acceleratethis low rate of hydrolysis (which is about 10-2 min-1) and to enable a transientburst of signalling activity, regulatory proteins like GAPs (GTPase activatingproteins) (Ahmadian et al., 1996) or NF-1(Neurofibromatosis Type 1) protein (McCormick, 1995), bind to the GTP-containingconformation and stimulate the GTPase activity more than 100-fold. The decreasinglevel of RAS-GTP, and hence, increasing level of RAS-GDP complexes result in aloss of the biological activity of RAS (see Fig. 1). In a normal cell, GAPs helpto keep most of p21RAS in an inactive GDP-bound state. The finding that overexpressionof non-mutated ras genes can also transform cells supports the idea that the abundanceof GAPs is limited. Overexpression of p21RAS could lead to saturation of the regulatoryproteins, resulting in a constitutive, deregulated activation of RAS proteinsand oncogenic transformation.
Another group of regulatory proteins involved in stimulating the transition ofRAS proteins from the inactive- to the active GTP-bound state are designated GuanineNucleotide Exchange Factors (GEFs) or RAS-GRFs (guanine nucleotide releasing factors)(Satoh and Kaziro, 1992). Normally, the release of GDP is regulated by the intracellularconcentration of GTP. An increase in the GTP concentration leads to an enhanceddissociation of GDP. GEFs catalyze the dissociation of GDP (see Fig.1). A ligand-freeRAS protein immediately binds GTP, because it is 10-fold more abundant in thecytosol than GDP.

Figure 1

Figure 1 Mechanism of RAS regulation
The activity of RAS proteins is regulated by a cycle of guanine nucleotide bindingand hydrolysis. In the active state p21 is bound to GTP, in the inactive to GDP.GEF (Guanine Nucleotide Exchange Factor) promotes dissociation of GDP and acts asa positive regulator; GAP (GTPase activating protein) promotes hydrolysis of GTPand acts asa negative regulator. Pi, inorganic phosphate.

Structure of RAS proteins

The alignment of their primary amino acid sequence clearly indicates the presenceof four domains within the RAS molecules. The first domain includes 85 amino acidsat the N-terminus which are found to be identical in H-, K-, and N-ras, demonstratinga high degree of conservation. The following 80 amino acids form a second domain, showingless conservation (70-80%) within the RAS proteins. The third domain spans the restof the molecule, except for the last four amino acids, and represents a hypervariableregion. The highly conserved carboxy-terminal motif CAAX (where C stands for cysteine,A for any aliphatic residue, and X for any uncharged amino acid) is the result ofposttranslational modifications and forms the last domain.

For more accurate identification of biologically relevant regions of p21RAS and forthe interpretation of activating mutations, X-crystallographic analysis of GDP- andGTP-bound RAS molecules and in vitro mutagenesis studies with mutated or truncatedRAS proteins were performed. As a result of these studies, the catalytic domain was identifiedbetween residues 1 to 171, including the region involved in guanine nucleotide bindingwhere residues 10-16 and 56-59 interact with b- and c-phosphate, and residues 116-119 and 152-165 interact with the guanine base., The so called core effector region(located between residues 32-40), represents an essential element for all interactionswith putative downstream effectors and the GAPs. A region encompassing the last four amino acids at the C-terminus (residues 186-189), was shown to be essential forthe attachment of p21RAS to the plasma membrane.

Comparison of the crystal structure of RAS-GTP (as indicated in Fig.2) and RAS-GDPcomplexes revealed that switching between the active and the inactive state isassociated with a conformational change of two regions, designated as switch I(residues 30-38), overlapping with the core effector region, and switch II (60-76).Binding of the neutralizing antibody Y13-259 to residues 63-73, inhibits the GTP-GDPchange, indicating that this conformational change is necessary for the transitionof RAS from the GDP- to the GTP-bound state and vice versa (Milburn et al., 1990;Scheffzek et al., 1997).

Figure 2

Figure 2 Topological structure of p21
The polypeptide chain of RAS p21 consists of six b-strands and five a-helices. Loop 1, alias phosphate-binding (P-) loop (residues 10 to 16), switch regions I (30 to 37), including loop 2 with adjacent residues, and II (60 to 67), including loop 4 and a-helix 2, represent the active center of the molecule and are involved in the binding interaction between p21RAS and GTP. N stands for the amino terminal, C for the carboxy terminal end.
(modified figure reprinted from Seminars in Cancer Biology vol 3, (4), F Wittinghofer, Tree-dimentional structure of p21H-ras and its implications, p189-198, 1992, by permission of the publisher Academic Press).

Activating point mutations have been localized in codons 12, 13, 59, 61, 63, 116, 117, 119, and 146 (Barbacid, 1990). All of these alterations occur at or near the guanine nucleotide binding sites. The effects of point mutations are either reduced GTPase activity (if amino acids 12, 13, 59, 61, 63 are involved), so that oncogenic RAS mutants are locked in the active GTP-bound state, or decreased nucleotide affinity, and hence, increased exchange of bound GDP for cytosolic GTP (if amino acids 116, 117, 119 or 146 are affected). The inefficient deactivation of the active GTP-bound RAS proteins is intensified by the inability of GAPs to stimulate the conversion to the inactive, GDP-bound state. All point mutations cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of constitutively active, GTP-bound RAS protein, and thus contributing to a malignant cell phenotype.

Incidence of ras mutations

(see also the appendix)

Activating ras mutations can be found in human malignancies with an overall frequencyof 15-20%. A high incidence of ras gene mutations has been reported in malignanttumors of the pancreas (80-90%, K-ras) (Ballas et al., 1988; Smit et al., 1988),in colorectal carcinomas (30-60%, K-ras)(Breivik J et al., 1994; Spandidos et al., 1996), in non-melanoma skin cancer(30-50%, H-ras) (Barbacid, 1990; Rodenhuis, 1992), in hematopoietic neoplasiaof myeloid origin (18-30%, K-and N-ras) (Breivik et al., 1994; Nakagawa et al.,1992; Neubauer et al., 1994; Satoh and Kaziro, 1992), and in seminoma(25-40%, K-ras) (Mulder et al., 1989; Ridanpaa et al., 1993). In other tumors,a mutant ras gene is found at a lower frequency: for example, in breastcarcinoma (0-12%, K-ras) (Rochlitz et al., 1989; Spandidos, 1987), glioblastomaand neuroblastoma (0-10%, K- and N-ras)(Ballas et al., 1988; Brustle et al., 1996; Ireland, 1989).

---

Appendix : RAS mutations in various cancers and bibliography

---

H-RAS mutations

Tumor	Frequency (%)	Reference
Stomach	0-40	(Deng et al., 1991; Kim et al., 1997; Miki et al., 1991; Nanus et al., 1990; Victor et al., 1990)
Urinary Bladder	0-65	(Hong et al., 1996; Malone et al., 1985; Olderoy et al., 1998; Saito et al., 1997; Visvanathan et al., 1988)
Prostate	0-10	(Carter et al., 1990; Gumerlock et al., 1991; Konishi et al., 1997; Shiraishi et al., 1998)
Skin	0-45	(Campbell et al., 1993; Tormanen and Pfeifer, 1992)
Thyroid	0-60	(Bouras et al., 1998; Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine et al., 1989; Suarez et al., 1988)
Breast	0-10	(Kraus et al., 1984; Spandidos, 1987)
Head and neck	0-30	(Clark et al., 1993; Kiaris et al., 1995; Rumsby et al., 1990; Saranath et al., 1991)
Endometrium	5	(Varras et al., 1996)

---

K-RAS mutations

Tumor	Frequency (%)	Reference
Pancreas	80-90	(Almoguera et al., 1988; Smit et al., 1988; Watanabe et al., 1996)
Colon and rectum	25-60	(Boughdady et al., 1992; Breivik et al., 1994; Burmer et al., 1991; Halter et al., 1992; Kojima et al., 1997; Oudejans et al., 1991; Spandidos et al., 1996; Ward et al., 1998; Yamagata et al., 1994)
Lung	25-60	(Husgafvel-Pursiainen et al., 1992; Rodenhuis and Slebos, 1992; Rodenhuis et al., 1997; Sagawa et al., 1998; Suzuki et al., 1990)
Prostate	0-25	(Capella et al., 1991; Carter et al., 1990; Gumerlock et al., 1991; Konishi et al., 1992; Konishi et al., 1997; Shiraishi et al., 1998)
Skin	0-25	(Albino et al., 1991; Shukla et al., 1989)
Thyroid	0-60	(Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine et al., 1989; Suarez et al., 1988)
Liver	10-25	(Challen et al., 1992; Marion et al., 1991; Tada et al., 1990; Tada et al., 1992)
Ovary	0-50	(Enomoto et al., 1991; Ichikawa et al., 1994; Teneriello et al., 1993)
Endometrium	10-40	(Duggan et al., 1994; Enomoto et al., 1991; Ignar-Trowbridge et al., 1992; Mizuuchi et al., 1992; Sasaki et al., 1993; Semczuk et al., 1997; Varras et al., 1996)
Kidney	0-50	(Nagata et al., 1990; Skalkeas et al., 1991)
Brain	0-15	(Ballas et al., 1988; Ballas et al., 1988; Brustle et al., 1996; Ireland, 1989; Maltzman et al., 1997)
Testis (Seminoma)	10-45	(Moul et al., 1992; Mulder et al., 1989; Ridanpaa et al., 1993)
Leukemia (ANLL, MDS)	5-15	(Nakagawa et al., 1992; Neubauer et al., 1994; Padua et al., 1998; Sheng et al., 1997)
Urinary Bladder	5	(Olderoy et al., 1998)
Head and neck	10	(Rathcke et al., 1996; Rumsby et al., 1990)
Breast	10	(Dawson et al., 1996)

---

N-RAS mutations

Tumor	Frequency (%)	Reference
Leukemia ANLL, MDS	20-40	(De Melo et al., 1997; Nakagawa et al., 1992; Neubauer et al., 1994; Padua et al., 1998; de Souza Fernandez et al., 1998; Syvanen et al., 1992)
Leukemia CML,ALL	0-10	(Watzinger et al., 1994; Yokota et al., 1998)
Brain	0-15	(Ballas et al., 1988; Bos, 1988; Brustle et al., 1996; Ireland, 1989; Maltzman et al., 1997)
Skin	0-20	(Albino et al., 1984; Mooy et al., 1991; Soparker et al., 1993; van't Veer et al., 1989)
Thyroid	0-60	(Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine et al., 1989; Suarez et al., 1988)
Testis	0-40	(Moul et al., 1992; Mulder et al., 1989; Ridanpaa et al., 1993)
Stomach	(gastric tumors) 5	(Kim et al., 1997)
Liver	0-15	(Challen et al., 1992; Tada et al., 1990; Tada et al., 1992)

Bibliography

Structural differences in the minimal catalytic domains of the GTPase-activating proteins p120GAP and neurofibromin.

Ahmadian MR, Wiesmüller L, Lautwein A, Bischoff FR, Wittinghofer A

The Journal of biological chemistry. 1996 ; 271 (27) : 16409-16415.

PMID 8663212

Lack of evidence of Ki-ras codon 12 mutations in melanocytic lesions.

Albino AP, Nanus DM, Davis ML, McNutt NS

Journal of cutaneous pathology. 1991 ; 18 (4) : 273-278.

PMID 1939786

Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity?

Albino AP, Le Strange R, Oliff AI, Furth ME, Old LJ

Nature. 1984 ; 308 (5954) : 69-72.

PMID 6700714

Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.

Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M

Cell. 1988 ; 53 (4) : 549-554.

PMID 2453289

Incidence of ras gene mutations in neuroblastoma.

Ballas K, Lyons J, Janssen JW, Bartram CR

European journal of pediatrics. 1988 ; 147 (3) : 313-314.

PMID 3292251

ras oncogenes: their role in neoplasia.

Barbacid M

European journal of clinical investigation. 1990 ; 20 (3) : 225-235.

PMID 2114981

The ras gene family and human carcinogenesis.

Bos JL

Mutation research. 1988 ; 195 (3) : 255-271.

PMID 3283542

K-ras gene mutations in adenomas and carcinomas of the colon.

Boughdady IS, Kinsella AR, Haboubi NY, Schofield PF

Surgical oncology. 1992 ; 1 (4) : 275-282.

PMID 1341261

Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers.

Bouras M, Bertholon J, Dutrieux-Berger N, Parvaz P, Paulin C, Revol A

European journal of endocrinology / European Federation of Endocrine Societies. 1998 ; 139 (2) : 209-216.

PMID 9724079

K-ras mutation in colorectal cancer: relations to patient age, sex and tumour location.

Breivik J, Meling GI, Spurkland A, Rognum TO, Gaudernack G

British journal of cancer. 1994 ; 69 (2) : 367-371.

PMID 8297737

Primitive neuroectodermal tumors after prophylactic central nervous system irradiation in children. Association with an activated K-ras gene.

Brüstle O, Ohgaki H, Schmitt HP, Walter GF, Ostertag H, Kleihues P

Cancer. 1992 ; 69 (9) : 2385-2392.

PMID 1314130

Frequency and spectrum of c-Ki-ras mutations in human sporadic colon carcinoma, carcinomas arising in ulcerative colitis, and pancreatic adenocarcinoma.

Burmer GC, Rabinovitch PS, Loeb LA

Environmental health perspectives. 1991 ; 93 : 27-31.

PMID 1773797

Codon 12 Harvey-ras mutations are rare events in non-melanoma human skin cancer.

Campbell C, Quinn AG, Rees JL

The British journal of dermatology. 1993 ; 128 (2) : 111-114.

PMID 8096149

Ras oncogene mutations in thyroid tumors: polymerase chain reaction-restriction-fragment-length polymorphism analysis from paraffin-embedded tissues.

Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J

Diagnostic molecular pathology : the American journal of surgical pathology, part B. 1996 ; 5 (1) : 45-52.

PMID 8919545

Frequency and spectrum of mutations at codons 12 and 13 of the c-K-ras gene in human tumors.

Capella G, Cronauer-Mitra S, Pienado MA, Perucho M

Environmental health perspectives. 1991 ; 93 : 125-131.

PMID 1685441

ras gene mutations in human prostate cancer.

Carter BS, Epstein JI, Isaacs WB

Cancer research. 1990 ; 50 (21) : 6830-6832.

PMID 2208148

Transforming function of proto-ras genes depends on heterologous promoters and is enhanced by specific point mutations.

Chakraborty AK, Cichutek K, Duesberg PH

Proceedings of the National Academy of Sciences of the United States of America. 1991 ; 88 (6) : 2217-2221.

PMID 2006160

Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas.

Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF

Journal of hepatology. 1992 ; 14 (2-3) : 342-346.

PMID 1323601

The absence of Harvey ras mutations during development and progression of squamous cell carcinomas of the head and neck.

Clark LJ, Edington K, Swan IR, McLay KA, Newlands WJ, Wills LC, Young HA, Johnston PW, Mitchell R, Robertson G

British journal of cancer. 1993 ; 68 (3) : 617-620.

PMID 8353052

ras and p53 genes in male breast cancer.

Dawson PJ, Schroer KR, Wolman SR

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1996 ; 9 (4) : 367-370.

PMID 8729973

N-ras gene point mutations in Brazilian acute myelogenous leukemia patients correlate with a poor prognosis.

De Melo MB, Lorand-Metze I, Lima CS, Saad ST, Costa FF

Leukemia & lymphoma. 1997 ; 24 (3-4) : 309-317.

PMID 9156660

Correlation of N-ras point mutations with specific chromosomal abnormalities in primary myelodysplastic syndrome.

de Souza Fernandez T, Menezes de Souza J, Macedo Silva ML, Tabak D, Abdelhay E

Leukemia research. 1998 ; 22 (2) : 125-134.

PMID 9593469

Correlation of mutations of oncogene C-Ha-ras at codon 12 with metastasis and survival of gastric cancer patients.

Deng GR, Liu XH, Wang JR

Oncogene research. 1991 ; 6 (1) : 33-38.

PMID 1671796

Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma.

Duggan BD, Felix JC, Muderspach LI, Tsao JL, Shibata DK

Cancer research. 1994 ; 54 (6) : 1604-1607.

PMID 8137266

K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.

Enomoto T, Weghorst CM, Inoue M, Tanizawa O, Rice JM

The American journal of pathology. 1991 ; 139 (4) : 777-785.

PMID 1656759

K-ras activation in premalignant and malignant epithelial lesions of the human uterus.

Enomoto T, Inoue M, Perantoni AO, Buzard GS, Miki H, Tanizawa O, Rice JM

Cancer research. 1991 ; 51 (19) : 5308-5314.

PMID 1913654

A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases.

Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio G

Nature. 1987 ; 328 (6126) : 170-172.

PMID 3600795

Activated ras alleles in human carcinoma of the prostate are rare.

Gumerlock PH, Poonamallee UR, Meyers FJ, deVere White RW

Cancer research. 1991 ; 51 (6) : 1632-1637.

PMID 1998954

Lack of ras mutations and prediction of long-term survival in carcinoma of the colon.

Halter SA, Webb L, Rose J

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1992 ; 5 (2) : 131-134.

PMID 1574489

A PCR-RFLP method for the detection of activated H-ras oncogene with a point mutation at codon 12 and 61.

Hong SJ, Lee T, Park YS, Lee KO, Chung BH, Lee SH

Yonsei medical journal. 1996 ; 37 (6) : 371-379.

PMID 9048488

Detection of ras gene mutations in human lung cancer: comparison of two screening assays based on the polymerase chain reaction.

Husgafvel-Pursiainen K, Ridanpää M, Hackman P, Anttila S, Karjalainen A, Onfelt A, B&oring;rresen AL, Vainio H

Environmental health perspectives. 1992 ; 98 : 183-185.

PMID 1486847

Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors.

Ichikawa Y, Nishida M, Suzuki H, Yoshida S, Tsunoda H, Kubo T, Uchida K, Miwa M

Cancer research. 1994 ; 54 (1) : 33-35.

PMID 8261457

Mutations of the Ki-ras oncogene in endometrial carcinoma.

Ignar-Trowbridge D, Risinger JI, Dent GA, Kohler M, Berchuck A, McLachlan JA, Boyd J

American journal of obstetrics and gynecology. 1992 ; 167 (1) : 227-232.

PMID 1442931

Activated N-ras oncogenes in human neuroblastoma.

Ireland CM

Cancer research. 1989 ; 49 (20) : 5530-5533.

PMID 2676145

The Ras signal transduction pathway.

Khosravi-Far R, Der CJ

Cancer metastasis reviews. 1994 ; 13 (1) : 67-89.

PMID 8143346

Mutations, expression and genomic instability of the H-ras proto-oncogene in squamous cell carcinomas of the head and neck.

Kiaris H, Spandidos DA, Jones AS, Vaughan ED, Field JK

British journal of cancer. 1995 ; 72 (1) : 123-128.

PMID 7599040

Kiaris H, Spandidos DA

Int J Oncol. 1999 ; 7 : page 413.

Mutation of ras oncogene in gastric adenocarcinoma: association with histological phenotype.

Kim TY, Bang YJ, Kim WS, Kang SH, Lee KU, Choe KJ, Kim NK

Anticancer research. 1997 ; 17 (2B) : 1335-1339.

PMID 9137494

Ki-ras point mutation in different types of colorectal carcinomas in early stages.

Kojima M, Konishi F, Tsukamoto T, Yamashita K, Kanazawa K

Diseases of the colon and rectum. 1997 ; 40 (2) : 161-167.

PMID 9075750

K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men.

Konishi N, Enomoto T, Buzard G, Ohshima M, Ward JM, Rice JM

Cancer. 1992 ; 69 (9) : 2293-2299.

PMID 1562975

Comparison of ras activation in prostate carcinoma in Japanese and American men.

Konishi N, Hiasa Y, Tsuzuki T, Tao M, Enomoto T, Miller GJ

The Prostate. 1997 ; 30 (1) : 53-57.

PMID 9018336

A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient.

Kraus MH, Yuasa Y, Aaronson SA

Proceedings of the National Academy of Sciences of the United States of America. 1984 ; 81 (17) : 5384-5388.

PMID 6089200

Activated ras oncogenes in human thyroid cancers.

Lemoine NR, Mayall ES, Wyllie FS, Farr CJ, Hughes D, Padua RA, Thurston V, Williams ED, Wynford-Thomas D

Cancer research. 1988 ; 48 (16) : 4459-4463.

PMID 3293774

High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis.

Lemoine NR, Mayall ES, Wyllie FS, Williams ED, Goyns M, Stringer B, Wynford-Thomas D

Oncogene. 1989 ; 4 (2) : 159-164.

PMID 2648253

c-Ha-ras gene bidirectional promoter expressed in vitro: location and regulation.

Lowndes NF, Paul J, Wu J, Allan M

Molecular and cellular biology. 1989 ; 9 (9) : 3758-3770.

PMID 2674682

Oncogenes and bladder cancer.

Malone PR, Visvanathan KV, Ponder BA, Shearer RJ, Summerhayes IC

British journal of urology. 1985 ; 57 (6) : 664-667.

PMID 4084726

Ras oncogene mutations in childhood brain tumors.

Maltzman TH, Mueller BA, Schroeder J, Rutledge JC, Patterson K, Preston-Martin S, Faustman EM

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1997 ; 6 (4) : 239-243.

PMID 9107428

ras activation in experimental carcinogenesis.

Mangues R, Pellicer A

Seminars in cancer biology. 1992 ; 3 (4) : 229-239.

PMID 1421167

Activation of Ki-ras gene by point mutation in human liver angiosarcoma associated with vinyl chloride exposure.

Marion MJ, Froment O, Trépo C

Molecular carcinogenesis. 1991 ; 4 (6) : 450-454.

PMID 1793483

Ras signaling and NF1.

McCormick F

Current opinion in genetics & development. 1995 ; 5 (1) : 51-55.

PMID 7749326

K-ras activation in gastric epithelial tumors in Japanese.

Miki H, Ohmori M, Perantoni AO, Enomoto T

Cancer letters. 1991 ; 58 (1-2) : 107-113.

PMID 2049776

Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins.

Milburn MV, Tong L, deVos AM, Brünger A, Yamaizumi Z, Nishimura S, Kim SH

Science (New York, N.Y.). 1990 ; 247 (4945) : 939-945.

PMID 2406906

Clinical implications of K-ras mutations in malignant epithelial tumors of the endometrium.

Mizuuchi H, Nasim S, Kudo R, Silverberg SG, Greenhouse S, Garrett CT

Cancer research. 1992 ; 52 (10) : 2777-2781.

PMID 1581890

No N-ras mutations in human uveal melanoma: the role of ultraviolet light revisited.

Mooy CM, Van der Helm MJ, Van der Kwast TH, De Jong PT, Ruiter DJ, Zwarthoff EC

British journal of cancer. 1991 ; 64 (2) : 411-413.

PMID 1892776

Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization.

Moul JW, Theune SM, Chang EH

Genes, chromosomes & cancer. 1992 ; 5 (2) : 109-118.

PMID 1381946

Activated ras genes in human seminoma: evidence for tumor heterogeneity.

Mulder MP, Keijzer W, Verkerk A, Boot AJ, Prins ME, Splinter TA, Bos JL

Oncogene. 1989 ; 4 (11) : 1345-1351.

PMID 2682461

Point mutations of c-ras genes in human bladder cancer and kidney cancer.

Nagata Y, Abe M, Kobayashi K, Saiki S, Kotake T, Yoshikawa K, Ueda R, Nakayama E, Shiku H

Japanese journal of cancer research : Gann. 1990 ; 81 (1) : 22-27.

PMID 2108944

Multiple point mutation of N-ras and K-ras oncogenes in myelodysplastic syndrome and acute myelogenous leukemia.

Nakagawa T, Saitoh S, Imoto S, Itoh M, Tsutsumi M, Hikiji K, Nakamura H, Matozaki S, Ogawa R, Nakao Y

Oncology. 1992 ; 49 (2) : 114-122.

PMID 1574246

Infrequent point mutations of ras oncogenes in gastric cancers.

Nanus DM, Kelsen DP, Mentle IR, Altorki N, Albino AP

Gastroenterology. 1990 ; 98 (4) : 955-960.

PMID 2179035

Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia.

Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA, Mayer RJ, Ball ED, Wurster-Hill D, Bloomfield CD

Blood. 1994 ; 83 (6) : 1603-1611.

PMID 8123851

Human cancer and cellular oncogenes.

Nishimura S, Sekiya T

The Biochemical journal. 1987 ; 243 (2) : 313-327.

PMID 3307760

Low-frequency mutation of Ha-ras and Ki-ras oncogenes in transitional cell carcinoma of the bladder.

Older&oring; G, Daehlin L, Ogreid D

Anticancer research. 1998 ; 18 (4A) : 2675-2678.

PMID 9703927

Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver.

Oudejans JJ, Slebos RJ, Zoetmulder FA, Mooi WJ, Rodenhuis S

International journal of cancer. Journal international du cancer. 1991 ; 49 (6) : 875-879.

PMID 1959991

RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up.

Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, Ridge S, Carter G, White D, Oscier D, Chevret S, West R

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1998 ; 12 (6) : 887-892.

PMID 9639416

[Incidence of point mutations in Ki-ras codon 12 and 13 in squamous epithelial carcinomas of the head-neck region]

Rathcke IO, Gottschlich S, Görögh T, Lippert BM, Werner JA

Laryngo- rhino- otologie. 1996 ; 75 (8) : 465-470.

PMID 8962608

K-ras oncogene codon 12 point mutations in testicular cancer.

Ridanpää M, Lothe RA, Onfelt A, Fosså S, B&oring;rresen AL, Husgafvel-Pursiainen K

Environmental health perspectives. 1993 ; 101 Suppl 3 : 185-187.

PMID 8143614

Incidence of activating ras oncogene mutations associated with primary and metastatic human breast cancer.

Rochlitz CF, Scott GK, Dodson JM, Liu E, Dollbaum C, Smith HS, Benz CC

Cancer research. 1989 ; 49 (2) : 357-360.

PMID 2642738

Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study.

Rodenhuis S, Boerrigter L, Top B, Slebos RJ, Mooi WJ, van't Veer L, van Zandwijk N

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1997 ; 15 (1) : 285-291.

PMID 8996154

Clinical significance of ras oncogene activation in human lung cancer.

Rodenhuis S, Slebos RJ

Cancer research. 1992 ; 52 (9 Suppl) : 2665s-2669s.

PMID 1562997

ras and human tumors.

Rodenhuis S

Seminars in cancer biology. 1992 ; 3 (4) : 241-247.

PMID 1421168

Low incidence of ras oncogene activation in human squamous cell carcinomas.

Rumsby G, Carter RL, Gusterson BA

British journal of cancer. 1990 ; 61 (3) : 365-368.

PMID 2183872

K-ras point mutation occurs in the early stage of carcinogenesis in lung cancer.

Sagawa M, Saito Y, Fujimura S, Linnoila RI

British journal of cancer. 1998 ; 77 (5) : 720-723.

PMID 9514049

Screening of H-ras gene point mutations in 50 cases of bladder carcinoma.

Saito S, Hata M, Fukuyama R, Sakai K, Kudoh J, Tazaki H, Shimizu N

International journal of urology : official journal of the Japanese Urological Association. 1997 ; 4 (2) : 178-185.

PMID 9179693

High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing tobacco-related human oral carcinoma in India.

Saranath D, Chang SE, Bhoite LT, Panchal RG, Kerr IB, Mehta AR, Johnson NW, Deo MG

British journal of cancer. 1991 ; 63 (4) : 573-578.

PMID 2021541

Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma.

Sasaki H, Nishii H, Takahashi H, Tada A, Furusato M, Terashima Y, Siegal GP, Parker SL, Kohler MF, Berchuck A

Cancer research. 1993 ; 53 (8) : 1906-1910.

PMID 8467512

Ras in signal transduction.

Satoh T, Kaziro Y

Seminars in cancer biology. 1992 ; 3 (4) : 169-177.

PMID 1421161

The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

Scheffzek K, Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F, Wittinghofer A

Science (New York, N.Y.). 1997 ; 277 (5324) : 333-338.

PMID 9219684

Detection of K-ras mutations in cancerous lesions of human endometrium.

Semczuk A, Berbéc H, Kostuch M, Kotarski J, Wojcierowski J

European journal of gynaecological oncology. 1997 ; 18 (1) : 80-83.

PMID 9061333

Mutations of the RAS genes in childhood acute myeloid leukemia, myelodysplastic syndrome and juvenile chronic myelocytic leukemia.

Sheng XM, Kawamura M, Ohnishi H, Ida K, Hanada R, Kojima S, Kobayashi M, Bessho F, Yanagisawa M, Hayashi Y

Leukemia research. 1997 ; 21 (8) : 697-701.

PMID 9379676

Mutations of ras genes are relatively frequent in Japanese prostate cancers: pointing to genetic differences between populations.

Shiraishi T, Muneyuki T, Fukutome K, Ito H, Kotake T, Watanabe M, Yatani R

Anticancer research. 1998 ; 18 (4B) : 2789-2792.

PMID 9713462

ras mutations in human melanotic lesions: K-ras activation is a frequent and early event in melanoma development.

Shukla VK, Hughes DC, Hughes LE, McCormick F, Padua RA

Oncogene research. 1989 ; 5 (2) : 121-127.

PMID 2691957

K-ras oncogene mutations in neoplasias of kidney transplanted patients: preliminary results with a new technique.

Skalkeas GD, Spandidos DA, Kostakis A, Balafouta-Tseleni S, Choremi E, Iliopoulos D, Haliassos A

Anticancer research. 1991 ; 11 (6) : 2091-2093.

PMID 1685646

KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas.

Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL

Nucleic acids research. 1988 ; 16 (16) : 7773-7782.

PMID 3047672

Investigation of the role of the ras protooncogene point mutation in human uveal melanomas.

Soparker CN, O'Brien JM, Albert DM

Investigative ophthalmology & visual science. 1993 ; 34 (7) : 2203-2209.

PMID 8505202

Spandidos DA et al

Tumori. 1996 ; 81 : page 7.

Oncogene activation in malignant transformation: a study of H-ras in human breast cancer.

Spandidos DA

Anticancer research. 1987 ; 7 (5B) : 991-996.

PMID 3435051

Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes.

Stanley LA

Toxicology. 1995 ; 96 (3) : 173-194.

PMID 7900159

Detection of activated ras oncogenes in human thyroid carcinomas.

Su´rez HG, Du Villard JA, Caillou B, Schlumberger M, Tubiana M, Parmentier C, Monier R

Oncogene. 1988 ; 2 (4) : 403-406.

PMID 3283656

Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products.

Suzuki Y, Orita M, Shiraishi M, Hayashi K, Sekiya T

Oncogene. 1990 ; 5 (7) : 1037-1043.

PMID 2197591

N-ras gene mutations in acute myeloid leukemia: accurate detection by solid-phase minisequencing.

Syvänen AC, Söderlund H, Laaksonen E, Bengtström M, Turunen M, Palotie A

International journal of cancer. Journal international du cancer. 1992 ; 50 (5) : 713-718.

PMID 1544704

High incidence of ras gene mutation in intrahepatic cholangiocarcinoma.

Tada M, Omata M, Ohto M

Cancer. 1992 ; 69 (5) : 1115-1118.

PMID 1739910

Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing.

Tada M, Omata M, Ohto M

Cancer research. 1990 ; 50 (4) : 1121-1124.

PMID 2153451

p53 and Ki-ras gene mutations in epithelial ovarian neoplasms.

Teneriello MG, Ebina M, Linnoila RI, Henry M, Nash JD, Park RC, Birrer MJ

Cancer research. 1993 ; 53 (13) : 3103-3108.

PMID 8319218

Mapping of UV photoproducts within ras proto-oncogenes in UV-irradiated cells: correlation with mutations in human skin cancer.

Törmä VT, Pfeifer GP

Oncogene. 1992 ; 7 (9) : 1729-1736.

PMID 1501884

N-ras mutations in human cutaneous melanoma from sun-exposed body sites.

van 't Veer LJ, Burgering BM, Versteeg R, Boot AJ, Ruiter DJ, Osanto S, Schrier PI, Bos JL

Molecular and cellular biology. 1989 ; 9 (7) : 3114-3116.

PMID 2674680

ras gene mutations in human endometrial carcinoma.

Varras MN, Koffa M, Koumantakis E, Ergazaki M, Protopapa E, Michalas S, Spandidos DA

Oncology. 1996 ; 53 (6) : 505-510.

PMID 8960147

No evidence for point mutations in codons 12, 13, and 61 of the ras gene in a high-incidence area for esophageal and gastric cancers.

Victor T, Du Toit R, Jordaan AM, Bester AJ, van Helden PD

Cancer research. 1990 ; 50 (16) : 4911-4914.

PMID 2199031

Preferential and novel activation of H-ras in human bladder carcinomas.

Visvanathan KV, Pocock RD, Summerhayes IC

Oncogene research. 1988 ; 3 (1) : 77-86.

PMID 3144694

Restriction endonuclease-mediated selective polymerase chain reaction: a novel assay for the detection of K-ras mutations in clinical samples.

Ward R, Hawkins N, O'Grady R, Sheehan C, O'Connor T, Impey H, Roberts N, Fuery C, Todd A

The American journal of pathology. 1998 ; 153 (2) : 373-379.

PMID 9708798

Detection of K-ras point mutations at codon 12 in pure pancreatic juice for the diagnosis of pancreatic cancer by PCR-RFLP analysis.

Watanabe H, Sawabu N, Songür Y, Yamaguchi Y, Yamakawa O, Satomura Y, Ohta H, Motoo Y, Okai T, Wakabayashi T

Pancreas. 1996 ; 12 (1) : 18-24.

PMID 8927616

Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia.

Watzinger F, Gaiger A, Karlic H, Becher R, Pillwein K, Lion T

Cancer research. 1994 ; 54 (14) : 3934-3938.

PMID 8033117

High sequence similarity within ras exons 1 and 2 in different mammalian species and phylogenetic divergence of the ras gene family.

Watzinger F, Mayr B, Haring E, Lion T

Mammalian genome : official journal of the International Mammalian Genome Society. 1998 ; 9 (3) : 214-219.

PMID 9501305

Lower incidence of K-ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas.

Yamagata S, Muto T, Uchida Y, Masaki T, Sawada T, Tsuno N, Hirooka T

Japanese journal of cancer research : Gann. 1994 ; 85 (2) : 147-151.

PMID 8144396

Mutational analysis of the N-ras gene in acute lymphoblastic leukemia: a study of 125 Japanese pediatric cases.

Yokota S, Nakao M, Horiike S, Seriu T, Iwai T, Kaneko H, Azuma H, Oka T, Takeda T, Watanabe A, Kikuta A, Asami K, Sekine I, Matsushita T, Tsuhciya T, Mimaya J, Koizumi S, Miyake M, Nishikawa K, Takaue Y, Kawano Y, Iwai A, Ishida Y, Matsumoto K, Fujimoto T

International journal of hematology. 1998 ; 67 (4) : 379-387.

PMID 9695411

Written	1999-03	Franz Watzinger, Thomas Lion
		Cancer Research Institute (CCRI), Kinderspitalgasse 6, A-1090 Vienna, Austria

Citation

This paper should be referenced as such :

Watzinger, F ; Lion, T

RAS family

Atlas Genet Cytogenet Oncol Haematol. 1999;3(2):116-123.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Deep/RasID20002.htm