Tumors proto-oncogenes

Anna CH, Maronpot RR, Pereira MA, et al. 1994. Ras proto-oncogene activation in dichloroacetic acid-, trichloroethylene-and tetrachloroethylene-induced liver tumors in B6C3F, mice. Carcinogenesis 15 2255-2261. 

ANDERSON M w, YOU M and REYNOLDS s H (1991) Proto-oncogene activation in rodent and human tumors , ADVExp Med Biol, 283, 235-43. 

Nagata Y, et al. Peptides derived from a wild-type murine proto-oncogene c-erbB-2/HER2/neu can induce CTL and tumor suppression in syngeneic hosts. J Immunol 1997 159 1336. 

Unlike tumor suppressors, in which loss-of-function mutations are required in both copies of the gene in a specific cell, a single gain-of-function mutation in a proto-oncogene is usually sufficient to give rise to cancer. 

Although the study of inherited cancer syndromes has led to the identification of a number of tumor suppressor genes and oncogenes, the inherited cancer syndromes are thought to account for only about 1% of all cancers. However, somatic (as opposed to germline) mutations in many of these tumor suppressors and proto-oncogenes play a key role in the causation of noninher-... 

Melanoma p/6 (tumor suppressor) and CDK4 (proto-oncogene, see Fig 11-5-3)... 

Each cell of the human body carries the potential to become cancerous in the form of its proto-oncogenes. The case of the src gene is far from unique. A great many proto-oncogenes have been discovered some of the best known are myc, myb, ras, fes, fins, fos, and jun (these names derive from the retrovirus in which they were discovered e.g., ras comes from a rat sarcoma virus and fes from a feline sarcoma virus). It follows that each of our cells harbors a number of protooncogenes, each of which may become activated and contribute to the formation of a tumor. 

By now, we have put together a lot of the cancer story. We know that cancer is a disease originating in a single cell that has overcome the normal limits to its growth and proliferation and that mutations in proto-oncogenes and/or tumor suppressor genes are required for this to happen. Beyond that, we know that multiple such mutations are usually required. 

Here are some insights into the functions of tumor suppressor genes and proto-oncogenes... 

Tumor cells differ from normal cells in one dramatic way they have lost the susceptibility to normal controls on cell proliferation. It should not surprise us then to learn that tumor suppressor genes and proto-oncogenes fall into one of three key categories. First, some oncogenic mutations directly affect cell proliferation. Second, other oncogenic mutations lead to loss of cell cycle control. Third, still other oncogenic mutations lead to genomic instability. 

Zachos G, Spandidos DA. Expression of ras proto-oncogenes regulation and implications in the development of human tumors. Crit Rev Oncol Hematol 1997 26 65-75. 

Shalaby, M.R., Shepard, H.M., Presta, L., et al. (1992). Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells over expressing the HER2 proto-oncogene. J. Exp. Med., 175, 217-225. 

Figure 6.51 Scheme showing the initiation and promotion of skin papillomas and carcinomas after treatment with DMBA and promotion with TPA (Fig. 53). The initiation converts (mutation) proto-oncogene ras to oncogene and promotion stimulates growth and division, forming a papilloma. Further exposure to initiator DMBA, alters (mutation) tumor suppressor gene p53 which collaborates with ras and causes carcinoma formation. See text for full explanation. Abbreviation DMBA, dimethylbenzanthracene. Source From Ref. 15.

The changes include activation of the proto-oncogene (K-ras) and inactivation of three tumor suppressor genes (Fig. 6.54). 

Of course, if the adducts are formed in sections of DNA that are "junk" DNA or spacing sections, there may be no consequence, even if not repaired. However, if the unrepaired DNA adduct(s) is in a section of DNA that is part of a tumor suppressor gene or a pro to-oncogene, then more serious changes may result such as the initiation of a tumor. In fact, benzo [a] pyrene does cause mutations (G to T trans vers ions) in the 12 th codon of one of the ras protooncogenes. This could convert the proto-oncogene into an active oncogene. 

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