| Oncogenes: mutant signal transducers
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| As mentioned above, mutations that lead to the uncontrolled proliferation of cancer cells can result either from disrup-tion of the control of normal cell division or, alternatively, from a reduction in the normal processes of terminal differentiation or apoptosis.
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| This distinction is reflected by the two main groups of genes targeted for mutation: oncogenes and tumor suppressor genes (Table 41.2).
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Table 41-2.
Factors involved in the uncontrolled proliferation of cancer cells. |
| Body_ID: None |
| Oncogene, transcription factors, and tumor suppressor genes (antioncogenes) |
| Body_ID: T041002.50 |
| Oncogene | Intracellular signaling role |
| Body_ID: T041002.100 |
| overexpressed growth factors | v-Sis encodes a sequence almost identical to the active PDGF-β |
| Body_ID: T041002.150 |
| | Int-2 and k-Fgf-hst are related to fibroblast growth factor (FGF) |
| Body_ID: T041002.200 |
| overexpressed and/or constitutively active growth factor receptors | v-ErbB is analogous to the activated cytoplasmic domain of EGF-receptor (EGF-R) |
| Body_ID: T041002.250 |
| | v-Fms is related to macrophage colony stimulating factor receptor (M-CSF-R) |
| Body_ID: T041002.300 |
| | v-kit is related to PDGF-R |
| Body_ID: T041002.350 |
| | Mas is related to the G-protein-coupled angiotensin receptor also, overexpression of normal receptors can lead to transformation |
| Body_ID: T041002.400 |
| G-proteins | mutated Gs (gsp) in pituitary/thyroid tumors |
| Body_ID: T041002.450 |
| | mutated Gi (gip2) in adrenocortical/ovarian tumors |
| Body_ID: T041002.500 |
| | Ras: mutated in 30% of human tumors |
| Body_ID: T041002.550 |
| kinases | Src, Abl: protein tyrosine kinases |
| Body_ID: T041002.600 |
| | Raf: serine-threonine kinase |
| Body_ID: T041002.650 |
| oncomodulin | calcium-binding protein similar to calmodulin, found |
| Body_ID: T041002.700 |
| | only in cancer cells |
| Body_ID: T041002.750 |
| growth regulation genes | Jun and Fos: transcription factors |
| Body_ID: T041002.800 |
| | Myc: a transcription factor regulating Cdc25 protein tyrosine phosphatase |
| Body_ID: T041002.850 |
| | Myb and Mos: regulate Gi/S-phase transition |
| Body_ID: T041002.900 |
| | Cdc2: regulation of S/M-phase transition |
| Body_ID: T041002.950 |
| | Bcl-2 family: cell survival |
| Body_ID: T041002.1000 |
| tumor suppressor genes | p53: most frequently mutated gene in human cancer; cell cycle and apoptosis regulator |
| Body_ID: T041002.1050 |
| | Rb gene; cell cycle regulator |
| Body_ID: T041002.1100 |
| | neurofibromatosis gene - analogous to Ras GTP-ase activating protein (GAP) |
| Body_ID: T041002.1150 |
| Oncogenes were first identified as viral genes that infect normal cells and transform them into tumor cells
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| For example, the Rous sarcoma virus, which is a retrovirus that causes connective tissue tumors in chickens, will infect and transform fibroblast cells grown in cell culture. The transformed cells outgrow the normal cells and exhibit a number of growth abnormalities, such as a loss of cell contact-mediated inhibition of growth and loss of anchorage-dependence of growth. In addition, the cells have a rounded appearance and can proliferate in the absence of growth factors. Moreover, the cells are immortal, do not senesce, and can induce tumor formation when injected into a suitable animal host.
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| The key to understanding cell transformation lay in the mutation of a normal cellular gene that controls cell growth. The use of mutant Rous sarcoma viruses that, despite multiplying normally, have lost the ability to transform host cells showed that it was the Src gene that was responsible for such cell transformation. The breakthrough in our understanding of how this single gene could transform cells in culture came when it became apparent that the viral oncogene was a mutated homolog of a normal cellular gene. This gene is now called the c-Src proto-oncogene and has been identified as a protein tyrosine kinase signal transducer involved in the normal control of cell growth. As expression of this gene is not essential to the survival of the retrovirus, it is likely that Src was accidentally incorporated by the virus from a previous host genome and was somehow mutated in the process. In the case of the Rous sarcoma virus, the introns normally present in c-Src are spliced out and, in addition, there are a number of mutations causing amino acid substitutions, resulting in a constitutively active enzyme.
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| Cell transformation can, however, also result from overexpression of an oncogene in an abnormally high number of copies, as a consequence of the gene being under the control of powerful promoters or enhancers in the viral genome. Alternatively, for retroviruses, DNA copies of the viral RNA inserted into the host genome at or near sites of proto-oncogenes (insertional mutation) can cause abnormal activation of these proto-oncogenes. In this situation, the altered genome is inherited by all progeny of the original host cell.
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| page 595 |  | | page 596 |
| Most human tumors are nonviral in origin, and arise from spontaneous or induced mutations. Approximately 85% of human tumors arise as a result of point or deletion mutations, rather than through viral involvement. The mutations may be spontaneous, or induced by carcinogens or radiation, resulting in overexpression or hyperactivity of the proto-oncogenes. In addition, karyotyping of tumor cells has shown, for example, that the conversion of the Abl (tyrosine kinase) proto-oncogene into an oncogene in CML results from a chromosomal translocation between chromosomes 9 and 22, with breakpoints in the Abl and Bcr genes, respectively, leading to the generation of a chromosome called the
Philadelphia chromosome. This translocation results in the generation of a fusion protein comprising the N-terminus of Bcr and the C-terminus of Abl. The Abl kinase domain of this fusion protein is hyperactive and drives the abnormal proliferation of a clone of hemopoietic progenitors in the bone marrow. In other cases, the translocation brings the oncogene under the control of an inappropriate promoter. For example, in Burkitt's lymphoma, overexpression of the Myc gene occurs through its translocation into the vicinity of one of the Ig loci. Because Myc normally acts as a nuclear proliferative signal, overexpression of Myc induces the cell to divide, even under conditions that would normally dictate growth arrest.
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| Oncogene actions are dominant and mutation in only one allele is therefore sufficient to transform culture cells
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| However, studies in transgenic mice overexpressing mutiple oncogenes have illustrated the point, made above, that human cancers are usually generated after the accumulation of mutations over several years. For example, transgenic mice overexpressing either the Myc or Ras oncogenes typically exhibit some tissues that are abnormally large. Occasionally, with age, some of these mice develop a few tumors, in a manner that is consistent with the expression of an inherited oncogene that increases the risk of accumulating further mutations and, hence, of initiating cancers. However, the vast majority of these transgenic cells do not develop any cancers. In contrast, double transgenic mice overexpressing both the Myc and the Ras oncogenes develop cancers at a much greater rate - a phenomenon known as oncogene collaboration. An example of such synergistic action in human cancers is provided by B cell lymphoma, which relies on cooperation between overexpressed Myc (to drive inappropriate cell division) and Bcl-2 (to inhibit apoptosis and promote B cell survival).
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