Oncogene

TABLE 23-15 Some Oncogenes Found in Human Tumors  

N-ras mutation Signal transduction Guanine diphosphate (GDP)/ guanine triphosphate (GTP) binding protein Acute myeloid leukemia, neuroblastoma 

K-rfls mutation Signal transduction GDP/GTP binding protein Leukemia, lymphoma 

The c-myc gene is the proto-oncogene of avian myelocytoma virus. It binds to DNA and is involved in transcription regulation. The gene product, p62, is located in the nucleus of transformed cells, and levels of c-myc correlate with the rate of cell division. The c-myc protein is essential for DNA replication and enhances mRNA transcription. Activation of the c-myc gene is associated with B- and T-ceH lymphoma, sarcomas, and endotheliomas. In leukemias and lymphomas, increased c-myc expression may be due to amplification or chromosomal translocation of the gene. In acute T-celi leukemias, there is an (8 14) (q24 qll) translocation that 

The HER-2/new gene (also known as c-erbB-2) is named for its association with neural tumors (new). 

The cellular form of oncogenes (known as c-oncogenes or proto-oncogenes) code for proteins involved in controlling growth and differentiation processes. They only become oncogenes if their sequence has been altered by mutations (see p. 256), deletions, and other processes, or when excessive amounts of the gene products have been produced as a result of overexpression. 

A feature common to all oncogenes is the fact that they code for proteins involved in signal transduction processes. The genes are designated using three-letter abbreviations that 

Ligands such as growth factors and cytokines, which promote cell proliferation. 

Membrane receptors of the 1-helix type with tyrosine kinase activity, which can bind growth factors and hormones (see p. 394). 

GTP-binding proteins. This group includes the G proteins in the strict sense and related proteins such as Ras (see p. 388), the product of the oncogene c-ras. 

Evidence for the first oncogene was found when certain mutants of RSV failed to transform cells at high temperature but did transform cells at low temperature. The mutant virus replicated well at both temperatures. This means that the virus contained a tem-perature-sensitive mutation in a gene that coded for a sarcoma-producing protein, that is, for v-src. 

Normal cells also were found to contain src-like genes when their DNA was hybridized with labeled nucleic acid probes from the v-src gene. As with other cellular genes, the c-onc genes were interrupted with introns. v-Onc genes lack introns. Consequently, in the distant past c-onc genes must have been transferred to the retroviruses. If the transfer had been from the virus to the cell, c-onc genes probably would not contain introns. 

The oncogene v-erbB, unlike c-erbB, codes for a shortened form of the EGF receptor protein. Usually the binding of EGF is required to turn on the tyrosine kinase activity of the EGF receptor protein, the one coded by c-erbB. However, the tyrosine kinase activity of the receptor derived from v-erbB is switched on permanently, even in the absence of EGF. The uncontrolled grqwth characteristic of cancer cells results. 

Other oncogenes code for proteins that bind guanine nucleotides, and others code for nuclear proteins. The guanine nucleotide-binding proteins, the so-called G proteins, affect several key reactions. Some G proteins are stimulatory, whereas others are inhibitory. For example, they link hormone receptors to adenylate cyclase, they translocate 

TABLE 9.4 EXAMPLES OF PROMOTERS WITH THEIR ASSOCIATED NEOPLASMS IN HUMANS.  

The EIA protein of adenovirus binds to and inactivates the product of the retinoblastoma (RB) gene — an antioncogene. The RB protein in some way acts to control cell proliferation and its inactivation has been implicated in a number of different human tumours (White et al., 1988 Weinberg, 1988). 

Tumourogenicity can also be induced by overproduction and mutation of the p53 protein which appears to be an antioncogene product similar to that of the RB gene (Finlay et al., 1989). The altered p53 protein binds tightly to the transforming proteins of 

SV40 and adenovirus and this may indicate how they exert their effect (Eliyahu et al., 1985 Lane, 1984 Wang et al., 1989). 

At this point, there is an interaction with a very important 21-kDa protein. This protein, called p21 or just Ras, is involved in about 30% of human tumors. The designation Ras comes from Rat sarcoma, the original tissue in which it was discovered. The Ras family of proteins are GTP-binding 

A Representative List of Proto-Oncogenes Implicated in Human Tumors  

Adapted from Bishop, J. M. 1991, Molecular themes in oncogenesis. Cell64.235-248. 

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Eadier reports of a link between testicular cancer and DMF exposure have not been corroborated ia a study of 4000 Du Pont employees (34). Very recendy, inhalation studies ia mice and rats have shown no oncogenic effect from DMF (35). The International Agency for Research on Cancer (lARC) has concluded that evidence associating DMF with cancer ia animals is "iaadequate," but has classified DMF as "possibly carciaogenic to humans" (Group 2B) (36). 

Many human diseases are caused when certain proteins are either over- or underexpressed. Eor example, breast cancer can be induced by overexpressing certain cellular oncogenes within mammary tissue. To study the disease, researchers produce a line of transgenic mice that synthesize an abnormal amount of the same protein. This leads to symptoms of the disease in mice that are similar to what is found in humans. A protein can be overexpressed by inserting a DNA constmct with a strong promotor. Conversely, underexpression of a protein can be achieved by inserting a DNA constmct that makes antisense RNA. This latter blocks protein synthesis because the antisense RNA binds and inactivates the sense mRNA that codes for the protein. Once a line of mice is developed, treatments are studied in mice before these therapies are appHed to humans. 

J. M. Smith and co-workers, "Methyl Methacrylate Subchronic, Chronic and Oncogenic Inhalation Safety Evaluation Studies," Mbstracts of the Eighteenth Mnnual Meeting of the Society of Toxicology, New Orleans, La., 1979. 

The relationship between the two receptors for NGF is complex and not yet completely understood. It has been suggested that the functional form of the NGF receptor is a heterodimer of p75 and pl40 proteins. BDNF and NT-3 bind to p75, but the functional receptors for these neurotrophins are the proto-oncogene products of and trkQ. 

The streptovaricins inhibit the reverse transcriptase of some RNA oncogenic vimses that may be involved in the process of viral transformation (see Antiviral agents). The atropisostreptovaricins again have similar activities to the corresponding natural isomers. The streptovals and streptovarone exhibit gready improved activity against reverse transcriptase relative to the streptovaricins (85), but their in vitro activities were low (86). The damavaricins also inhibit reverse transcriptase (4) as well as tumor cell growth (87). 

Biotechnology. Particular attention must be paid to the detection of DNA in all finished biotechnology products because of the possibiUty that such DNA could be incorporated into the human genome and thus become a potential oncogene. The absence of DNA at the picogram-per-dose level should be demonstrated in order to assure the safety of biotechnology products (157). 

Retroviridae Types B and C Oncovirus numerous leukemias, including friend. oncogenic of lower animals... 

Gross Moloney, Rauscher rous sarcoma, HIV oncogenic of fowl, aids... 

The leucine zipper motif (see Chapter 3) was first recognized in the amino acid sequences of a yeast transcription factor GCN4, the mammalian transcription factor C/EBP, and three oncogene products, Fos, Jun and Myc, which also act as transcription factors. When the sequences of these proteins are plotted on a helical wheel, a remarkable pattern of leucine residues... 

Jumak, F. Structure of the GDP domain of EF-Tu and location of the amino acids homologous to ras oncogene proteins. Science 230 32-36, 1985. 

Pai, E.F., et al. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature 341 209-214,... 

Scheffzek, K., et al. The Ras-RasGAP complex structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277 333-338, 1997. 

Some occupational hygiene aspects of man-made mineral fibres and new technology fibres Safe handling requirements dunng explosive, propellant and pyrotechnic manufacture Simplified calculations of blast induced injuries and damage Laboratory work with chemical carcinogens and oncogenes Rosin (colophony) a review... 

TABLE 5.22 Important Oncogenes and Tumor Suppressor Genes in Human Cancers... 

Woodget, J. R., 1991. A common denominator linking glycogen metabolism, nuclear oncogenes, and development. Trends in Biochemical Sciences 16 177-181. 

Thiophene, 2,2-bithiophene, and 2,2, 5, 2"-terthiophene derivatives from Chinese medicinal plants as oncogene signal transduction inhibitors (proteinki-nase C inhibitors) 99PAC1101. 

Ravichandran KS (2001) Signaling via She family adapter proteins. Oncogene 20 6322-6330... 

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