Oncogenes in Retroviruses and Cells: Biochemistry and Molecular Genetics

doi:10.1016/S0065-230X(08)60199-2

Advances in Cancer Research

Volume 47, 1986, Pages 99-188

https://doi.org/10.1016/S0065-230X(08)60199-2 Get rights and content

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This chapter discusses the biochemistry and the molecular genetics of a particular set of oncogenes, originally identified as transforming genes of avian acute leukemia viruses. This group of retroviruses played a key role in establishing the concept that normal cells contain multiple genes with the potential to become dominant oncogenic determinants. Six different cell-derived oncogenes were identified in this virus group alone, myc oncogene among them— by now one of the most intensively studied genes implicated in viral and nonviral carcinogenesis. In addition, several basic features and some unique variations of oncogene structure and expression were first diagnosed in this virus group. Also, a crucial progress in the search for physiological functions of cellular alleles of oncogenes was achieved by the discovery of close sequence homology between an oncogene of an avian acute leukemia virus and a human gene encoding a growth factor receptor, Hence, the oncogenes of avian acute leukemia viruses serve in the chapter as a model case to review the current knowledge about the structure and function of eukaryotic genes involved in malignant cell transformation.

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Members of the virus families Retroviridae and Hepadnaviridae use reverse transcriptase (RT) to synthesize a DNA copy of their genomic and pregenomic RNA, respectively, during the viral life cycle. A group of viruses belonging to Retroviridae (“acute transforming” retroviruses) as well as human hepatitis B virus (HBV), the prototype member of Hepadnaviridae (hepadnaviruses) are able to cause malignant neoplasms in infected hosts, due to the expression of pleiotropic “transforming proteins” encoded by the genomes of these reverse-transcribing tumor viruses. In this review we wish to compare the common and unique features of replication strategies characteristic of acute transforming retroviruses and HBV and summarize data related to the origin and evolution of their viral oncogenes either via transduction of cellular genes, or by accumulation of mutations in viral sequences that create a new open reading frame (overprinting). The exons of cellular genes (proto-onc genes or c-onc genes) incorporated into the genome of acute transforming retroviruses are regularly affected by deletions resulting in the expression of truncated viral oncoproteins which are frequently dysregulated compared to their cellular counterparts. These retroviral transforming proteins alter the behavior of their target cells (malignant transformation). HBx, a pleiotropic protein of HBV, regulates virus replication and contributes to hepatocarcinogenesis. In contrast to the v-onc genes of acute transforming retroviruses, the viral gene encoding the full-length, wild-type HBx (wtHBx) protein does not have a cellular counterpart. Mutations and deletions frequently affect, however, the HBV genome as well, resulting in the expression of truncated HBx proteins (trHBx) in liver cells. Truncated, especially C-terminal truncated variants of HBx (Ct-HBX proteins), may facilitate initiation and progression of liver carcinoma.
Oncogenes
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Oncogenes are eukaryotic genes that have the potential to become dominant oncogenic determinants in tumorigenesis. They are mutant alleles of normal cellular genes, termed protooncogenes, that are preserved in evolution and have essential physiological functions in normal cells. The protein products of most protooncogenes are components of signal transduction cascades, including growth factors, hormone receptors, G proteins, protein kinases, or transcription factors regulating fundamental cellular processes such as growth, proliferation, differentiation, metabolism, and apoptosis. The transcriptome and proteome changes triggered by these signaling events modulate the cellular phenotype in response to metabolic, developmental, or growth-related requirements. Oncogenic activation of protooncogenes abrogates this normal cellular regulation and leads to tumorigenesis. The activation mechanisms include retroviral transduction, transcriptional activation by insertional mutagenesis, somatic mutation within the coding region, chromosomal translocation, and DNA amplification.
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MC29 avian myelocytomatosis virus is an acute leukemia virus and the prototype of the MC29-subgroup of the avian leukosis-sarcoma genus of type C retroviruses. It causes myelocytomatosis, endotheliomas, liver and kidney carcinomas, and sarcomas in chickens. Biochemical and genetic analyses of the RNA genome of MC29 led to the discovery of the myc oncogene. The MC29 genome contains partial complements of the essential virion genes gag and env, and v-myc as the transforming principle. The single protein product of MC29, p110^gag-myc, is a hybrid translational product of the partial gag gene and the v-myc sequences. The retroviral v-myc oncogene is a transduced mutant allele of the cellular protooncogene c-myc. The protein product of c-myc (Myc) is a bHLH-Zip protein, forms heterodimers with the bHLH-Zip protein Max, binds to specific DNA sequence elements (E-boxes), and is the central part of a transcription factor network controlling fundamental cellular processes like growth, metabolism, proliferation, differentiation, and apoptosis. Mutation and deregulation of c-myc is a frequent event in human tumorigenesis, occurring in about 30% of all human cancers. Myc and Max proteins were identified in early diploblastic organisms, suggesting that the principal functions of the Myc master regulator arose very early in metazoan evolution.
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Citation Excerpt :
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Oncogenes in Retroviruses and Cells: Biochemistry and Molecular Genetics

Publisher Summary

Cell

Cell

Virology

Virology

Cell

Adv. Cancer Res.

Lancet

Virology

Virology

Cell

Cell

Cell

Cell

Virology

Virology

Cell

Virology

J. Biol. Chem.

Exp. Cell Res.

Cell

Cell

Proc. Natl. Acad. Sci. U.S.A.

Nature (London)

Mol. Cell. Biol.

J. Natl. Cancer Inst. (U.S.)

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Nature (London)

Proc. Natl. Acad. Sci. U.S.A.

J. Virol.

Nature (London)

Proc. Natl. Acad. Sci. U.S.A.

Nature (London)

Proc. Natl. Acad. Sci. U.S.A.

“Viral Oncology”

“Unifying Concepts of Leukemia”

Nature (London)

J. Virol.

EMBO J.

Nature (London)

Proc. Natl. Acad. Sci. U.S.A.

EMBO J.

J. Virol.

Cell

Annu. Rev. Biochem.

“RNA Tumor Viruses”

Cold Spring Harbor Symp. Quant. Biol.

“Mechanisms of Viral Leukaemogenesis”

Proc. Natl. Acad. Sci. U.S.A.