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Oncogenes
Oncogenes M Hartl and K Bister, University of Innsbruck, Innsbruck, Austria
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by N Haites, volume 3, pp 1370–1372, © 2001, Elsevier Inc.
Glossary Aneuploidy Abnormal number of chromosomes usually accompanied by chromosomal rearrangements; chromosomal abnormality typically observed in cancer cells. Env Retroviral structural gene encoding envelope glycoproteins including transmembrane and surface components. Gag Retroviral structural gene encoding group-specific antigens including matrix, capsid, and nucleocapsid proteins. Gene expression Conversion of genetic information into a functional gene product by transcription of DNA and translation of RNA. The gene product is either an RNA molecule (ribosomal RNA, transfer RNA, and microRNA) or a protein (translated from messenger RNA). Mutation Change in the genomic DNA sequence by nucleotide substitution, deletion, or insertion, caused by radiation, chemicals, carcinogens, viruses, transposons, or errors during DNA replication. Pol Retroviral structural gene encoding reverse transcriptase and integrase.
Protooncogene Cellular gene (c-onc) with oncogenic potential; mutant alleles act as dominant oncogenic determinants. Retroviral oncogene Transduced mutant allele (v-onc) of a cellular gene (c-onc) with oncogenic potential. Retroviral transduction Incorporation of cellular genes into retroviral genomes by genetic recombination between virus and host cell. Signal transduction Process in which an extracellular signal molecule interacts with a cellular receptor, thereby activating intracellular signaling events; signals transmitted to the nucleus lead to transcriptome alterations caused by the modulation of transcription factors. Tumor suppressor gene Cellular gene encoding a protein with inhibitory effects on cell cycle progression and/or promoting effects on apoptosis; mutant alleles are typically recessive; loss of heterozygosity leads to tumorigenesis. Warburg effect Increased conversion of glucose to lactate in tumor cells, even in the presence of oxygen (aerobic glycolysis).
Genetic Basis of Cancer
Origin and Activation of Oncogenes
Cancer cells differ from normal cells by distinct biological and biochemical features such as unrestrained proliferation, insensitivity toward antiproliferative signals, immortality, increased angiogenesis, cell death resistance, aneuploidy, meta static potential, and metabolic abnormalities such as increased aerobic glycolysis. The concept that initiation, maintenance, and progression of cancerous growth are based on genetic alterations in the neoplastic cell received compelling support by the discov eries of genes that have the potential to act as dominant oncogenic determinants in tumorigenesis (oncogenes), and of genes with the opposite function, that is, protection of a cell from malignant growth (tumor suppressor genes). Mutant alleles of tumor suppressor genes are usually recessive, and initiation of tumorigenesis requires loss of heterozygosity by functional inac tivation also of the second allele. Oncogenes were originally discovered as oncogenic determinants in the RNA genomes of highly oncogenic retroviruses that induce rapid tumor formation in animals and morphological transformation of animal cells in tissue culture. Retroviral oncogenes represent transduced mutant alleles (v-onc) of normal cellular genes (c-onc; protooncogene) that have been highly conserved in metazoan evolution and fulfill essential physiological functions in cell growth and development. In contrast to the cell-derived oncogenes of retroviruses, oncogenes of DNA tumor viruses are true viral genes. Here, only oncogenes derived from cellular protooncogenes are discussed.
In 1970, the first oncogene was identified by pioneering biochemical and genetic analyses of the RNA genome of a highly oncogenic chicken retrovirus, Rous sarcoma virus (RSV). Comparison of the RSV genome with that of nontransforming (transformation-defective) derivatives revealed that RSV contains genetic information other than the genes and control elements essential for retroviral replication. This additional gene, termed src (for sarcoma), was unequivocally defined as the transforming principle of RSV (Figure 1). The search for the origin of src led to the groundbreaking discovery that the viral oncogene (v-src) is derived from a normal cellular gene, the c-src protooncogene, by retroviral transduction, that is, recombination between virus and host cell during the retroviral life cycle. Guided by the semi nal work on the transforming principle of RSV, cell-derived oncogenes unrelated to src were identified in the genomes of other highly oncogenic retroviruses of birds and mammals. In all cases, retroviral transduction of cellular oncogenes leads to incorporation of only partial complements of the c-onc genes into the retroviral genome. In particular, terminal transcriptional control regions are always removed and replaced by retroviral control elements. Cellular oncogenes have also been discovered independently of retroviral transduction by direct experimental search for genetic changes in tumor cell DNA. These genetic alterations include functionally relevant mutations within the coding region, transcriptional activation by insertional muta genesis, chromosomal translocation, and gene amplification.
164
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 5
doi:10.1016/B978-0-12-374984-0.01089-5
Oncogenes
165
3�
5� gag
pol
env
gag
pol
env
5�
v-src
RSV
3� td RSV
1.0 kb
Figure 1 Discovery of the first oncogene (v-src) by genetic and biochemical comparison of the RNA genomes of oncogenic Rous sarcoma virus (RSV) and of transformation-defective (td) derivatives of RSV. Gag, pol, and env represent essential virion genes.
Several genes found to be affected by somatic mutations or rearrangements in tumor cell DNA proved to be c-onc alleles of independently isolated retroviral oncogenes. The overlaps between the groups of oncogenes identified by retroviral
transduction or by cellular mutational events support the notion that the number of cellular genes with oncogenic potential is limited. All mutational events that convert normal cellular protooncogenes into active oncogenes (Table 1) lead to one or
Table 1
Classification and functions of oncogenes
Onc
Activation mechanism
Species
Tumor type
Protein product
v-abl c-abl c-abl bcl-2 v-erbA v-erbB v-erbB c-erbB v-ets c-ets-1 v-fos v-fos v-jun int-1,2 int-2 v-mil v-raf v-myb v-myb c-myb v-myc v-myc c-myc c-myc c-myc N-myc L-myc erbB-2 v-rasH v-rasH c-rasH c-rasH v-rasK v-rasK c-rasK c-rasK rasN v-sis v-src
Abelson leukemia virus DNA translocation (bcr-abl) DNA amplification DNA translocation Avian erythroblastosis virus ES4 Avian erythroblastosis virus ES4 Insertional mutagenesis DNA amplification Avian erythroblastosis virus E26 DNA amplification FBJ osteogenic sarcoma virus Avian retrovirus NK24 Avian sarcoma virus 17 Insertional mutagenesis DNA amplification Avian carcinoma virus MH2 Murine sarcoma virus 3611 Avian myeloblastosis virus Insertional mutagenesis DNA amplification Avian myelocytomatosis virus MC29 Avian carcinoma virus MH2 Insertional mutagenesis DNA translocation DNA amplification DNA amplification DNA amplification DNA amplification Harvey sarcoma virus Insertional mutagenesis DNA amplification Chemical carcinogens Kirsten sarcoma virus Insertional mutagenesis DNA amplification Chemical carcinogens DNA amplification Simian sarcoma virus Rous sarcoma virus
Mouse Human Human Human Chicken Chicken Chicken Human Chicken Human Mouse Chicken Chicken Mouse Human Chicken Mouse Chicken Mouse Human Chicken Chicken Mouse Human Human Human Human Human Rat Chicken Human Rodents Rat Mouse Human Mouse Human Monkey Chicken
Leukemia CLL, ALL CML B-cell lymphoma Leukemia Leukemia Erythroleukemia Glioblastoma Leukemia Lymphoma Osteosarcoma Nephroblastoma Fibrosarcoma Mammary carcinoma Carcinoma Carcinoma Sarcoma Leukemia Myeloid leukemia Colon carcinoma Myelocytoma Carcinoma T-cell lymphoma Burkitt’s lymphoma Breast and lung carcinomas Neuroblastoma Lung carcinoma Breast and ovarian carcinomas Sarcoma Nephroblastoma Bladder carcinoma Carcinoma Sarcoma Leukemia Colon, pancreatic carcinoma Lung carcinoma Breast carcinoma, AML, ALL Sarcoma Sarcoma
Tyrosine kinase
Apoptosis inhibitor Cytosolic hormone receptor Receptor tyrosine kinase (EGF-R)
Transcription factor Transcription factor (AP-1) Transcription factor (AP-1) Growth factor Serine/threonine kinase Transcription factor
Transcription factor
Transcription factor Transcription factor Receptor tyrosine kinase (EGF-R) GTPase
GTPase
GTPase Growth factor (PDGF) Tyrosine kinase
ALL, acute lymphatic leukemia; AML, acute myelogenous leukemia; AP-1, activator protein-1; CLL, chronic lymphatic leukemia; CML, chronic myelogenous leukemia; EGF-R, epidermal growth factor receptor; GTP, guanosine triphosphate; Onc, oncogene; PDGF, platelet-derived growth factor.
166
Oncogenes
GF
Grb2
sm
Cytopla
RTK
AC
Ras SOS ATP Abl
cAMP
Raf/ Mil
MEK MAPK MEKK us
cle
Nu
DNA
Jun
Myc
Fos
Max
signaling, cell transformation, and tumorigenesis. Some of the prototype oncogenes have very broad pleiotropic effects on nearly all major cellular processes. For instance, the protein product (Myc) of the c-myc protooncogene constitutes the central hub of a transcriptional regulator network controlling the expression of probably 15% of all human genes, either by transcriptional activation or by repression. Myc is involved in the regulation of fundamental cellular processes such as growth control, metabolism, proliferation, differentiation, and apop tosis. Deregulation of c-myc leading to increased levels of the Myc protein is a frequent mutational event in human tumor igenesis, occurring in about 30% of all human cancers. Recently, complex hallmarks of cancer cells, such as genomic instability or reprogramming of energy metabolism, including increased aerobic glycolysis (Warburg effect), have also been attributed to oncogenic Myc function.
Target genes
Figure 2 Mitogenic signal transduction. The simplified cartoon shows key regulators in mitogenic signaling starting with growth factor (GF) binding to receptor tyrosine kinases (RTKs). The activated receptor interacts via adaptor proteins (Grb2 and SOS) with the guanine nucleotide exchange factor Ras, which then activates adenylate cyclase (AC), or the serine/threonine kinase Raf (Mil). The signal is then transmitted into the nucleus via mitogen-activated protein kinases (MAPK, MEK, and MEKK) leading to phosphorylation of sequence-specific DNA-binding proteins regulating the transcription of distinct target genes. Proteins encoded by oncogenes are labeled in red. cAMP, cyclic adenosine monophosphate.
more of these molecular effects: (1) an increase in protein expres sion due to increased mRNA synthesis or gene amplification, (2) mutations leading to increased (enzymatic) activity and/or loss of negative regulation, and (3) chromosomal translocation caus ing increased protein expression and/or generation of a fusion protein with oncogenic properties.
Function of Oncogene Protein Products The protein products of oncogenes typically represent compo nents of signal transduction pathways, including growth factors, growth factor receptors, GTPases, protein kinases, or transcription factors (Table 1, Figure 2). Oncogenic activation by deregulated expression or structural modifications of onco proteins can lead to constitutive activation of mitogenic
See also: Cancer Genetics; MC29 Avian Myelocytomatosis Virus; Retroviruses; Transcription Factors.
Further Reading Bister K and Jansen HW (1986) Oncogenes in retroviruses and cells: Biochemistry and molecular genetics. Advances in Cancer Research 47: 99–188. Croce CM (2008) Oncogenes and cancer. The New England Journal of Medicine 358: 502–511. Duesberg PH and Vogt PK (1970) Differences between the ribonucleic acids of transforming and nontransforming avian tumor viruses. Proceedings of the National Academy of Sciences of the United States of America 67: 1673–1680. Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70. Hanahan D and Weinberg RA (2011) Hallmarks of cancer: The next generation. Cell 144: 646–674. Levine AJ and Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330: 1340–1344. Parada LF, Tabin CJ, Shih C, and Weinberg RA (1982) Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297: 474–478. Prochownik EV and Li Y (2007) The ever expanding role for c-Myc in promoting genomic instability. Cell Cycle 6: 1024–1029. Shim H, Dolde C, Lewis BC, et al. (1997) c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proceedings of the National Academy of Sciences of the United States of America 94: 6658–6663. Stehelin D, Varmus HE, Bishop JM, and Vogt PK (1976) DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260: 170–173. Wang LH, Duesberg P, Beemon K, and Vogt PK (1975) Mapping RNase T1-resistant oligonucleotides of avian tumor virus RNAs: Sarcoma-specific oligonucleotides are near the poly(A) end and oligonucleotides common to sarcoma and transformationdefective viruses are at the poly(A) end. Journal of Virology 16: 1051–1070.
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by N Haites, volume 3, pp 1370–1372, © 2001, Elsevier Inc.
Glossary Aneuploidy Abnormal number of chromosomes usually accompanied by chromosomal rearrangements; chromosomal abnormality typically observed in cancer cells. Env Retroviral structural gene encoding envelope glycoproteins including transmembrane and surface components. Gag Retroviral structural gene encoding group-specific antigens including matrix, capsid, and nucleocapsid proteins. Gene expression Conversion of genetic information into a functional gene product by transcription of DNA and translation of RNA. The gene product is either an RNA molecule (ribosomal RNA, transfer RNA, and microRNA) or a protein (translated from messenger RNA). Mutation Change in the genomic DNA sequence by nucleotide substitution, deletion, or insertion, caused by radiation, chemicals, carcinogens, viruses, transposons, or errors during DNA replication. Pol Retroviral structural gene encoding reverse transcriptase and integrase.
Protooncogene Cellular gene (c-onc) with oncogenic potential; mutant alleles act as dominant oncogenic determinants. Retroviral oncogene Transduced mutant allele (v-onc) of a cellular gene (c-onc) with oncogenic potential. Retroviral transduction Incorporation of cellular genes into retroviral genomes by genetic recombination between virus and host cell. Signal transduction Process in which an extracellular signal molecule interacts with a cellular receptor, thereby activating intracellular signaling events; signals transmitted to the nucleus lead to transcriptome alterations caused by the modulation of transcription factors. Tumor suppressor gene Cellular gene encoding a protein with inhibitory effects on cell cycle progression and/or promoting effects on apoptosis; mutant alleles are typically recessive; loss of heterozygosity leads to tumorigenesis. Warburg effect Increased conversion of glucose to lactate in tumor cells, even in the presence of oxygen (aerobic glycolysis).
Genetic Basis of Cancer
Origin and Activation of Oncogenes
Cancer cells differ from normal cells by distinct biological and biochemical features such as unrestrained proliferation, insensitivity toward antiproliferative signals, immortality, increased angiogenesis, cell death resistance, aneuploidy, meta static potential, and metabolic abnormalities such as increased aerobic glycolysis. The concept that initiation, maintenance, and progression of cancerous growth are based on genetic alterations in the neoplastic cell received compelling support by the discov eries of genes that have the potential to act as dominant oncogenic determinants in tumorigenesis (oncogenes), and of genes with the opposite function, that is, protection of a cell from malignant growth (tumor suppressor genes). Mutant alleles of tumor suppressor genes are usually recessive, and initiation of tumorigenesis requires loss of heterozygosity by functional inac tivation also of the second allele. Oncogenes were originally discovered as oncogenic determinants in the RNA genomes of highly oncogenic retroviruses that induce rapid tumor formation in animals and morphological transformation of animal cells in tissue culture. Retroviral oncogenes represent transduced mutant alleles (v-onc) of normal cellular genes (c-onc; protooncogene) that have been highly conserved in metazoan evolution and fulfill essential physiological functions in cell growth and development. In contrast to the cell-derived oncogenes of retroviruses, oncogenes of DNA tumor viruses are true viral genes. Here, only oncogenes derived from cellular protooncogenes are discussed.
In 1970, the first oncogene was identified by pioneering biochemical and genetic analyses of the RNA genome of a highly oncogenic chicken retrovirus, Rous sarcoma virus (RSV). Comparison of the RSV genome with that of nontransforming (transformation-defective) derivatives revealed that RSV contains genetic information other than the genes and control elements essential for retroviral replication. This additional gene, termed src (for sarcoma), was unequivocally defined as the transforming principle of RSV (Figure 1). The search for the origin of src led to the groundbreaking discovery that the viral oncogene (v-src) is derived from a normal cellular gene, the c-src protooncogene, by retroviral transduction, that is, recombination between virus and host cell during the retroviral life cycle. Guided by the semi nal work on the transforming principle of RSV, cell-derived oncogenes unrelated to src were identified in the genomes of other highly oncogenic retroviruses of birds and mammals. In all cases, retroviral transduction of cellular oncogenes leads to incorporation of only partial complements of the c-onc genes into the retroviral genome. In particular, terminal transcriptional control regions are always removed and replaced by retroviral control elements. Cellular oncogenes have also been discovered independently of retroviral transduction by direct experimental search for genetic changes in tumor cell DNA. These genetic alterations include functionally relevant mutations within the coding region, transcriptional activation by insertional muta genesis, chromosomal translocation, and gene amplification.
164
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 5
doi:10.1016/B978-0-12-374984-0.01089-5
Oncogenes
165
3�
5� gag
pol
env
gag
pol
env
5�
v-src
RSV
3� td RSV
1.0 kb
Figure 1 Discovery of the first oncogene (v-src) by genetic and biochemical comparison of the RNA genomes of oncogenic Rous sarcoma virus (RSV) and of transformation-defective (td) derivatives of RSV. Gag, pol, and env represent essential virion genes.
Several genes found to be affected by somatic mutations or rearrangements in tumor cell DNA proved to be c-onc alleles of independently isolated retroviral oncogenes. The overlaps between the groups of oncogenes identified by retroviral
transduction or by cellular mutational events support the notion that the number of cellular genes with oncogenic potential is limited. All mutational events that convert normal cellular protooncogenes into active oncogenes (Table 1) lead to one or
Table 1
Classification and functions of oncogenes
Onc
Activation mechanism
Species
Tumor type
Protein product
v-abl c-abl c-abl bcl-2 v-erbA v-erbB v-erbB c-erbB v-ets c-ets-1 v-fos v-fos v-jun int-1,2 int-2 v-mil v-raf v-myb v-myb c-myb v-myc v-myc c-myc c-myc c-myc N-myc L-myc erbB-2 v-rasH v-rasH c-rasH c-rasH v-rasK v-rasK c-rasK c-rasK rasN v-sis v-src
Abelson leukemia virus DNA translocation (bcr-abl) DNA amplification DNA translocation Avian erythroblastosis virus ES4 Avian erythroblastosis virus ES4 Insertional mutagenesis DNA amplification Avian erythroblastosis virus E26 DNA amplification FBJ osteogenic sarcoma virus Avian retrovirus NK24 Avian sarcoma virus 17 Insertional mutagenesis DNA amplification Avian carcinoma virus MH2 Murine sarcoma virus 3611 Avian myeloblastosis virus Insertional mutagenesis DNA amplification Avian myelocytomatosis virus MC29 Avian carcinoma virus MH2 Insertional mutagenesis DNA translocation DNA amplification DNA amplification DNA amplification DNA amplification Harvey sarcoma virus Insertional mutagenesis DNA amplification Chemical carcinogens Kirsten sarcoma virus Insertional mutagenesis DNA amplification Chemical carcinogens DNA amplification Simian sarcoma virus Rous sarcoma virus
Mouse Human Human Human Chicken Chicken Chicken Human Chicken Human Mouse Chicken Chicken Mouse Human Chicken Mouse Chicken Mouse Human Chicken Chicken Mouse Human Human Human Human Human Rat Chicken Human Rodents Rat Mouse Human Mouse Human Monkey Chicken
Leukemia CLL, ALL CML B-cell lymphoma Leukemia Leukemia Erythroleukemia Glioblastoma Leukemia Lymphoma Osteosarcoma Nephroblastoma Fibrosarcoma Mammary carcinoma Carcinoma Carcinoma Sarcoma Leukemia Myeloid leukemia Colon carcinoma Myelocytoma Carcinoma T-cell lymphoma Burkitt’s lymphoma Breast and lung carcinomas Neuroblastoma Lung carcinoma Breast and ovarian carcinomas Sarcoma Nephroblastoma Bladder carcinoma Carcinoma Sarcoma Leukemia Colon, pancreatic carcinoma Lung carcinoma Breast carcinoma, AML, ALL Sarcoma Sarcoma
Tyrosine kinase
Apoptosis inhibitor Cytosolic hormone receptor Receptor tyrosine kinase (EGF-R)
Transcription factor Transcription factor (AP-1) Transcription factor (AP-1) Growth factor Serine/threonine kinase Transcription factor
Transcription factor
Transcription factor Transcription factor Receptor tyrosine kinase (EGF-R) GTPase
GTPase
GTPase Growth factor (PDGF) Tyrosine kinase
ALL, acute lymphatic leukemia; AML, acute myelogenous leukemia; AP-1, activator protein-1; CLL, chronic lymphatic leukemia; CML, chronic myelogenous leukemia; EGF-R, epidermal growth factor receptor; GTP, guanosine triphosphate; Onc, oncogene; PDGF, platelet-derived growth factor.
166
Oncogenes
GF
Grb2
sm
Cytopla
RTK
AC
Ras SOS ATP Abl
cAMP
Raf/ Mil
MEK MAPK MEKK us
cle
Nu
DNA
Jun
Myc
Fos
Max
signaling, cell transformation, and tumorigenesis. Some of the prototype oncogenes have very broad pleiotropic effects on nearly all major cellular processes. For instance, the protein product (Myc) of the c-myc protooncogene constitutes the central hub of a transcriptional regulator network controlling the expression of probably 15% of all human genes, either by transcriptional activation or by repression. Myc is involved in the regulation of fundamental cellular processes such as growth control, metabolism, proliferation, differentiation, and apop tosis. Deregulation of c-myc leading to increased levels of the Myc protein is a frequent mutational event in human tumor igenesis, occurring in about 30% of all human cancers. Recently, complex hallmarks of cancer cells, such as genomic instability or reprogramming of energy metabolism, including increased aerobic glycolysis (Warburg effect), have also been attributed to oncogenic Myc function.
Target genes
Figure 2 Mitogenic signal transduction. The simplified cartoon shows key regulators in mitogenic signaling starting with growth factor (GF) binding to receptor tyrosine kinases (RTKs). The activated receptor interacts via adaptor proteins (Grb2 and SOS) with the guanine nucleotide exchange factor Ras, which then activates adenylate cyclase (AC), or the serine/threonine kinase Raf (Mil). The signal is then transmitted into the nucleus via mitogen-activated protein kinases (MAPK, MEK, and MEKK) leading to phosphorylation of sequence-specific DNA-binding proteins regulating the transcription of distinct target genes. Proteins encoded by oncogenes are labeled in red. cAMP, cyclic adenosine monophosphate.
more of these molecular effects: (1) an increase in protein expres sion due to increased mRNA synthesis or gene amplification, (2) mutations leading to increased (enzymatic) activity and/or loss of negative regulation, and (3) chromosomal translocation caus ing increased protein expression and/or generation of a fusion protein with oncogenic properties.
Function of Oncogene Protein Products The protein products of oncogenes typically represent compo nents of signal transduction pathways, including growth factors, growth factor receptors, GTPases, protein kinases, or transcription factors (Table 1, Figure 2). Oncogenic activation by deregulated expression or structural modifications of onco proteins can lead to constitutive activation of mitogenic
See also: Cancer Genetics; MC29 Avian Myelocytomatosis Virus; Retroviruses; Transcription Factors.
Further Reading Bister K and Jansen HW (1986) Oncogenes in retroviruses and cells: Biochemistry and molecular genetics. Advances in Cancer Research 47: 99–188. Croce CM (2008) Oncogenes and cancer. The New England Journal of Medicine 358: 502–511. Duesberg PH and Vogt PK (1970) Differences between the ribonucleic acids of transforming and nontransforming avian tumor viruses. Proceedings of the National Academy of Sciences of the United States of America 67: 1673–1680. Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70. Hanahan D and Weinberg RA (2011) Hallmarks of cancer: The next generation. Cell 144: 646–674. Levine AJ and Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330: 1340–1344. Parada LF, Tabin CJ, Shih C, and Weinberg RA (1982) Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297: 474–478. Prochownik EV and Li Y (2007) The ever expanding role for c-Myc in promoting genomic instability. Cell Cycle 6: 1024–1029. Shim H, Dolde C, Lewis BC, et al. (1997) c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proceedings of the National Academy of Sciences of the United States of America 94: 6658–6663. Stehelin D, Varmus HE, Bishop JM, and Vogt PK (1976) DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260: 170–173. Wang LH, Duesberg P, Beemon K, and Vogt PK (1975) Mapping RNase T1-resistant oligonucleotides of avian tumor virus RNAs: Sarcoma-specific oligonucleotides are near the poly(A) end and oligonucleotides common to sarcoma and transformationdefective viruses are at the poly(A) end. Journal of Virology 16: 1051–1070.