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This work was funded by the following grants and associations: National Natural Science Foundations of China and , Hunan province natural science funds for Yong scholars JJ You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Paradoxical effects of DNA tumor virus oncogenes on epithelium-derived tumor cell fate during tumor progression and chemotherapy response.
Sig Transduct Target Ther 6, Download citation. Received : 27 June Revised : 23 September Accepted : 11 October Published : 26 November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative. Advanced search. Skip to main content Thank you for visiting nature. Download PDF. Subjects Cancer Tumour virus infections. Abstract Epstein-Barr virus EBV and human papillomavirus HPV infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma, respectively. Full size image. As already noted, many of the proteins encoded by proto-oncogenes regulate normal cell proliferation; in these cases, the elevated expression or activity of the corresponding oncogene proteins drives the uncontrolled proliferation of cancer cells.
Other oncogene products contribute to other aspects of the behavior of cancer cells, such as defective differentiation and failure to undergo programmed cell death.
The majority of oncogene proteins function as elements of the signaling pathways that regulate cell proliferation and survival in response to growth factor stimulation. These oncogene proteins include polypeptide growth factors , growth factor receptors, elements of intracellular signaling pathways, and transcription factors Figure Oncogenes and signal transduction.
Oncogene proteins act as growth factors e. The action of growth factors as oncogene proteins results from their abnormal expression, leading to a situation in which a tumor cell produces a growth factor to which it also responds. The result is autocrine stimulation of the growth factor-producing cell see Figure A large group of oncogenes encode growth factor receptors, most of which are protein-tyrosine kinases.
These receptors are frequently converted to oncogene proteins by alterations of their amino-terminal domains , which would normally bind extracellular growth factors. For example, the receptor for platelet-derived growth factor PDGF is converted to an oncogene in some human leukemias by a chromosome translocation in which the normal amino terminus of the PDGF receptor is replaced by the amino terminal sequences of a transcription factor called Tel Figure Alternatively, genes that encode some receptor protein-tyrosine kinases, such as erb B-2, are activated by gene amplification.
Other oncogenes including src and abl encode nonreceptor protein-tyrosine kinases that are constitutively activated by deletions or mutations of regulatory sequences. As discussed earlier, the mutations that convert ras proto-oncogenes to oncogenes result in constitutive Ras activity, which leads to activation of the MAP kinase pathway.
The raf gene can similarly be converted to an oncogene by deletions that result in loss of the amino-terminal regulatory domain of the Raf protein see Figure These deletions result in unregulated activity of the Raf protein kinase, which also leads to constitutive MAP kinase activation.
The MAP kinase pathway ultimately leads to the phosphorylation of transcription factors and alterations in gene expression. As might therefore be expected, many oncogenes encode transcriptional regulatory proteins that are normally induced in response to growth factor stimulation.
Fos and the product of another proto-oncogene, Jun , are components of the AP-1 transcription factor , which activates transcription of a number of target genes in growth factor-stimulated cells Figure Constitutive activity of AP-1, resulting from unregulated expression of either the Fos or Jun oncogene proteins, is sufficient to drive abnormal cell proliferation, leading to cell transformation.
The Myc proteins similarly function as transcription factors regulated by mitogenic stimuli, and abnormal expression of myc oncogenes contributes to the development of a variety of human tumors. Other transcription factors are frequently activated as oncogenes by chromosome translocations in human leukemias and lymphomas.
The AP-1 transcription factor. Fos and Jun dimerize to form AP-1, which activates transcription of a variety of growth factor-inducible genes. G protein-coupled receptors and G proteins also act as oncogenes in some human tumors Figure For example, mutations of the gene encoding the thyrotropin receptor convert it to an oncogene in thyroid tumors. Thyrotropin is a pituitary hormone that stimulates proliferation of thyroid cells through a G protein-coupled receptor that activates adenylyl cyclase.
Mutations of the thyrotropin receptor in thyroid tumors result in constitutive activity of the receptor, which then drives cell proliferation via activation of the cAMP signaling pathway. Likewise, the genes encoding G proteins can act as oncogenes in some cell types.
As might be expected, the gsp oncogene is involved in thyroid and pituitary tumors, where cAMP stimulates cell proliferation. Oncogenic activity of G protein-coupled receptors and G proteins. The thyrotropin receptor is coupled to adenylyl cyclase by G s. The intracellular signaling pathways activated by growth factor stimulation ultimately regulate components of the cell cycle machinery that promote progression through the restriction point in G 1.
The D-type cyclins are induced in response to growth factor stimulation and play a key role in coupling growth factor signaling to cell cycle progression see Figure Perhaps not surprisingly, the gene encoding cyclin D1 is a proto-oncogene , which can be activated as an oncogene called D 1 by chromosome translocation or gene amplification.
These alterations lead to constitutive expression of cyclin D1, which then drives cell proliferation in the absence of normal growth factor stimulation. Although most oncogenes stimulate cell proliferation, the oncogenic activity of some transcription factors instead results from inhibition of cell differentiation. As noted in Chapter 13, thyroid hormone and retinoic acid induce differentiation of a variety of cell types. These hormones diffuse through the plasma membrane and bind to intracellular receptors that act as transcriptional regulatory molecules.
In both cases, the mutated oncogene receptors appear to interfere with the action of their normal homologs, thereby blocking cell differentiation and maintaining the leukemic cells in an actively proliferating state Figure This biological observation has a direct clinical correlate: Patients with acute promyelocytic leukemia can be treated effectively by administration of retinoic acid, which induces differentiation and blocks continued cell proliferation.
As discussed earlier in this chapter, the failure of cancer cells to undergo programmed cell death , or apoptosis , is a critical factor in tumor development, and several oncogenes encode proteins that act to promote cell survival Figure The survival of most animal cells is dependent on growth factor stimulation, so those oncogenes that encode growth factors , growth factor receptors, and signaling proteins such as Ras act not only to stimulate cell proliferation, but also to prevent cell death.
The bcl -2 oncogene is generated by a chromosome translocation that results in elevated expression of Bcl-2, which blocks apoptosis and maintains cell survival under conditions that normally induce cell death. The identification of bcl -2 as an oncogene not only provided the first demonstration of the significance of programmed cell death in the development of cancer, but also led to the discovery of the role of Bcl-2 and related genes as central regulators of apoptosis in organisms ranging from C.
Oncogenes and cell survival. The oncogene proteins that signal cell survival include growth factors, growth factor receptors, PI 3-kinase, and Akt. By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed. Turn recording back on. National Center for Biotechnology Information , U.
Show details Cooper GM. Sunderland MA : Sinauer Associates ; Search term. Retroviral Oncogenes Viral oncogenes were first defined in RSV , which transforms chicken embryo fibroblasts in culture and induces large sarcomas within 1 to 2 weeks after inoculation into chickens Figure Figure Table
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