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Discovery of Oncogenes: the Advent of Molecular Cancer Research

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Discovery of Oncogenes: the Advent of Molecular Cancer Research COMMENTARY COMMENTARY Discovery of oncogenes: The advent of molecular cancer research Klaus Bister1 structural comparisons of the a and b subunits Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, of biologically cloned viruses, the transforming A-6020 Innsbruck, Austria principle was defined by the remarkably simple equation a − b = x and was later termed src td (for sarcoma). The first biochemical identifi- In their classic paper on the identification of defective ( ) mutant derivatives, they found cation of a cancer gene was achieved, initially the transforming principle of Rous sarcoma that all transforming virus stocks contained in a chicken virus. However, the principal proof virus (RSV) published 1970 in PNAS (1), two classes of RNA subunits, a larger one a b of a physical underpinning of the cancer gene Peter Duesberg at the University of California, ( ) and a smaller one ( ), whereas the non- hypothesis had tremendous impact on a fun- Berkeley, and Peter Vogt, then at the University transforming yet replication-competent mu- damental challenge of medicine, decoding the of Washington, Seattle, drew a seemingly sim- tants contained the smaller b subunits only. a molecular basis of human carcinogenesis. ple yet groundbreaking conclusion. When they Duesberg and Vogt concluded that the larger The genetic and biochemical investiga- analyzed the genomic RNAs of transforming, subunit contained the transforming princi- tions of the chicken tumor virus RSV and the acutely oncogenic RSV and of transformation- ple of RSV. Based on this and on subsequent persistent search for its transforming prin- ciple are a classic paradigm in cellular and molecular cancer research (2, 3). In 1911, Peyton Rous at the Rockefeller Institute in New York discovered the first virus—later termed RSV—that could induce solid tu- mors in infected fowl, demonstrated by ex- perimental transmission of sarcomas using cell-free filtrates of tumor extracts (4). This seminal discovery started the field of tumor virology (2, 3, 5). However, almost half a century had to pass before the first quanti- tative biological tools were developed to study the biology of RSV and its interaction with infected cells in detail. RSV is capable of transforming primary chicken embryo fi- broblasts in culture, and the focus assay devel- oped in 1958 by Howard Temin and Harry Rubin at the California Institute of Technol- ogy allowed a quantitative assessment of the virus–cell interaction leading to malignant cell transformation (6). The next crucial steps to- ward the identification of the underlying prin- ciple of RSV oncogenicity were based on classic genetics. The characterization of var- ious viral strains that induced different mor- phologies of transformed cells suggested that the phenotype of the cancer cell is controlled by the incoming genetic information carried by the viral genome. The isolation of RSV mutants that can transform cells but do not produce infectious progeny, or vice versa, can replicate but have lost cell transforming Fig. 1. Biochemical definition of src, the first oncogene. Panels A and B,above,arefromtheoriginalPNASpaper by Duesberg and Vogt (1). They show electropherograms of the 60–70S RNAs from two transforming strains of RSV, Schmidt-Ruppin (SR) and B77, before (A)andafter(B) heat-dissociation. Insets in A show the final sucrose gradient purifi- Author contributions: K.B. wrote the paper. cation of the RNAs before electrophoretic analysis. The heat-dissociated RNAs were resolved into two subunits with lower (a) The author declares no conflict of interest. and higher (b) electrophoretic mobility. Analyses of biologically cloned viruses revealed that the larger subunit represents the genomic RNA of transforming RSV, whereas the b subunit is the genome of transformation-defective (td)mutantsspon- This article is part of the special series of PNAS 100th Anniversary taneously segregating from RSV (1, 10). Subsequent mapping studies (10, 11) confirmed that the genomes of RSV and of td articles to commemorate exceptional research published in PNAS “ mutants share all replicative genes (gag, pol, env)andthatthesizedifference(a − b = x) is caused by the additional src over the last century. See the companion article, Differences be- gene at the 3′ end of the RSV genome. Cells infected by RSV become transformed (indicated by rounding) and produce tween the ribonucleic acids of transforming and nontransforming ” virus progeny (red star symbols), whereas td RSV replicates (green star symbols) but does not transform the host cell. avian tumor viruses on page 1673 in issue 4 of volume 67. A and B reproduced with permission from ref. 1. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1521145112 PNAS Early Edition | 1of2 Downloaded by guest on September 26, 2021 capacity, demonstrated that viral replication the whole field of tumor virology and cancer retroviruses. In two studies from the Vogt and and oncogenicity are genetically separable, in- genetics (12). Their finding—that the src gene Duesberg laboratories, also published in PNAS dependent functions of RSV (2, 3). A ground- of RSV (v-src) is in fact a transduced allele of in 1977 and 1979, analyses of the genomes of breaking leap forward came from studies of a cellular gene (c-src)pickedupbyrecombi- avian acute leukemia viruses MC29 and avian conditional mutants (7, 8). In 1970, Steve nation during the retroviral life cycle—is one erythroblastosis virus, using the biochemical ap- Martin at the University of California, Berkeley of the most influential discoveries in cancer proach described above, led to the discovery of isolated a temperature-sensitive mutant of research. It immediately converted the purely specific sequences unrelated to replicative genes RSV that did not transform cells at the non- virological matter of oncogenes to a cellular or to the prototypic src oncogene (17, 18). These permissive temperature but replicated nor- one, relevant for all animals and man, as was novel oncogenes were later shown to be derived mally, indicating the existence of a viral gene quickly shown by the identification of c-src in from cellular oncogenes, which today are known that is necessary for cell transformation but many species. Principally, any activating mu- as major drivers of human cancer, MYC,and dispensable for replication (8). tation or deregulation of cellular oncogenes, the ERBB/EGFR gene, respectively (2). While In the same year, a marvelous synergistic also termed proto-oncogenes in their normal src, myc,anderbB were originally discovered effort of biochemistry and virus genetics led to nonmutated form, could now lead to cancer, in avian tumor viruses (2, 19), other prominent the first physical identification of an oncogene, with or without viral involvement. The exper- oncogenes, like ras, were identified in murine reported in the classic paper by Duesberg and imental design for the discovery of c-src tumor viruses or in independent seminal exper- Vogt in PNAS (1). Their biochemical ap- exploited the availability of reverse transcrip- iments by direct transfection of human tumor proach in the hunt for the transforming prin- tion and the definition of v-src by the size cell DNA into recipient cells (2, 20). ciple made use of the availability of td deletion difference (a − b = x) of transforming and Having spent postdoctoral time both in the mutants of RSV and of nontransforming viruses td RSV genomes (Fig. 1; and see above). Syn- Vogt and Duesberg laboratories right at the associated with avian sarcoma or leukemia thesis of RSV cDNA and subtractive hybrid- time when all of this was happening, I can viruses (2). In essence, the experimental design ization with td RNA led to a src-specific DNA vividly recall the exciting, almost adventurous involved coelectrophoresis of viral RNAs from probe that was used for annealing experi- spirit of the oncogene discovery days. Partic- transforming and nontransforming avian ret- ments showing that normal cells contain se- ularly stimulating were the joint informal roviruses, including various strains of RSV and quences closely related to src in their genomic meetings of the Vogt, Duesberg, and Bishop/ td or associated viruses. Notably, current nucleic DNA (12). Subsequent reports on the exper- Varmus groups held at alternating California acid technologies, like reverse transcription, blot- imental recovery of transforming viruses by laboratory sites, where ideas, strategies, and ting, cloning, or sequencing, were not yet estab- recombination of td RSV carrying partial results were freely exchanged and crucial lished in those days. All of this had to be done v-src deletions with cellular sequences corrob- collaborations initiated. From the pioneering by metabolic labeling of infected cell cultures orated the close v-src/c-src relationship (13). discovery of the first oncogene in a chicken with radiolabeled precursors ([3H]uridine or For the landmark discovery of the cellular virus, oncogene research has developed into a 32 [ P]H3PO4), purification of viruses, extrac- origin of retroviral oncogenes, Bishop and central topic in human cancer genetics. Several tion of viral RNA, polyacrylamide gel electro- Varmus were awarded the Nobel Prize in Phys- oncogenes originally identified in retroviruses phoresis, gel slicing, and scintillation counting iology or Medicine in 1989. Following the are now recognized as major drivers in human of 1-mm gel slices. The results were as clear as identification of v-src and c-src,theimmuno- cancers, and drugs targeted at specific onco- compelling. After heat dissociation, the 60–70S logical detection and characterization of the src gene functions are used in cancer therapy (2). RNA complexes of all viruses able to trans- protein product as a tyrosine-specific protein Furthermore, many proto-oncogenes are es- form chicken embryo fibroblasts resolved into kinase with modular protein interaction do- sential genes involved in fundamental pro- two types of RNA species at variable ratios: a mains were further groundbreaking discoveries cesses in normal cells, like growth, metabolism, large a subunit and a smaller b subunit (Fig.
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