DNA tumour viruses

Cellular transformation by DNA tumour viruses in most cases has been shown to be the result of protein-protein interaction. Proteins encoded by the DNA tumour viruses, termed tumour antigens (T antigens), can interact with cellular proteins. This interaction effectively sequesters the cellular proteins away from their normal functional locations within the cell. The predominant types of protein sequestered by viral T antigens have been shown to be of the tumour-suppressor type. It is the loss of their normal suppressor functions that results in cellular transformation. 

About 20% of all cancers have been traced to tumour viruses, although the number of people infected is probably much larger than the number of people who actually develop cancer. Moreover, cancer-causing viruses may only be one of many contributing factors. DNA tumour viruses are probably more important as cancer-causing agents than RNA retroviruses (Table 17.1). 

Stow, N. D., Murray, M. D., and Stow, E. C. (1986). In Cancer Cells, Vol. 4 DNA Tumour Viruses Control of Gene Expression and Replication (M. Botchan, T. Grodzicker, and P. Sharp, Eds.), pp. 497-507. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. 

Animal virus vectors. Derivatives of the now well defined DNA tumour virus, SV40, have been used as vectors for foreign DNA. Rabbit globin cDNA, carried by one such vector, was properly transcribed and translated when... 

Baltimore D (1970) RNA-dependent DNA polymerase in virions of RNA tumour viruses. Nature 226 1209-1211... 

As pointed out above, nt1 receptors have been discovered in lymphoma cells selected for resistance to the cytolytic glucocorticoid effect. Since receptors from which the M domain had been eliminated by cDNA manipulation still function to some extent in transfection studies it was important to find out whether nt1 receptors would also be able to mediate some hormonal response. This was in fact observed when nt lymphoma variants were transfected with a DNA construct consisting of the LTR region of the mouse mammary tumour virus coupled to the gene for chloramphenicol acetyltransferase (U. Gehring and H. Losert, unpublished experiments). Hormonal induction of enzyme activity was consistently observed but was low, as one might expect. 

As has already been mentioned, some lipophilic rifamycins and some strepto-varicins and geldanamycins affect the growth of cells transformed by RNA tumour viruses or the RNA-dependent DNA polymerase (reverse transcriptase) characteristic of these viruses. Again, high drug concentrations are needed to produce an effect and only partial, but never absolute, selectivity of enzyme inhibition has been found. 

Tumour cells also can arise by non-genetic means through the actions of specific tumour viruses. Tumour viruses are of two distinct types, those with DNA genomes (e.g. papilloma and adenoviruses) and those with RNA genomes (termed retroviruses). RNA tumour viruses are common in chickens, mice and cats but rare in humans. The only currently known human retroviruses are the human T-ceU leukaemia viruses and the related retrovirus (see Chapter 15). 

Conditions for optimal recoveries of poly(A) containing RNA, with minimal contamination from rRNA, were investigated. The poly(A) fractions isolated were effective as an RNA template for the synthesis of complementary DNA with the RNA-dependent DNA polymerase of avian myeloblastosis virus. Poly(dT)-cellulose has also been used both in the purification of a 14 S messenger RNA for the immunoglobulin light chain from microsomes of MOPC 41 mouse myeloma that appeared to code for a precursor protein [117], and in the purification of RNA-dependent DNA polymerase from RNA tumour virus [118]. An example of the use of oligo(dT)-cellulose is provided by the purification of a viral specific RNA from sarcoma virus-transformed nonproducer cells [119]. 

Reverse transcriptase (from avian or murine RNA tumour viruses) [9068-38-6] Mr 170,000, [EC 2.7.7.49]. This enzyme produces the complementary DNA from the RNA (as template). These are purified by solubilising the virus with non-ionic detergents. Lysed virions are adsorbed on DEAE-cellulose or DEAE-Sephadex columns, and the enzymes are eluted with a salt gradient, then chromatographed on a phosphocellulose column and fractions with enzyme activity are eluted in a salt gradient. They are also purified from other viral proteins by affinity chromatography on a pyran-Sepharose column. [Verna Biochim Biophys Acta 473 1 1977, Smith Methods Enzymol 65 560 1980, see commercial catalogues for other transcriptases.]... 

Striking examples were given in Section 4.0.2 where extra selectivity is derived from the difference between enzymes responsible for the replication of virally nominated nucleic acids and those being used by the uninfected cell. Apart from these examples of the control of,DNA viruses, possibilities exist for RNA viruses because the following enzymes, specified by these viruses, are quite different from those used by the uninfected cell RNA transcriptases of influenza viruses, RNA replicases of the enteroviruses and rhinoviruses, and the reverse transcriptases of RNA tumour viruses. 

Complementary DNA Synthesis.—In 1970 it was established that the RNA tumour viruses replicate, via a DNA intermediate, employing an enzyme coded for by the viral genome. -The enzyme, RNA-dependent DNA polymerase (E.C. 2.1.1.1.), popularly known as reverse transcriptase, proved to have low specificity and to be able to transcribe efficiently and faithfully any RNA into a complementary DNA (cDNA), provided a preformed primer was available to initiate transcription (for a review, see ref. 16). By use of this enzyme it was possible to synthesize in vitro highly radioactive DNA complementary to isolated messenger RNAs. 

Williams GT, Morimoto RI (1990) Maximal stress-induced transcription from the human HSP70 promoter requires interactions with the basal promoter elements independent of rotational alignment. Mol Cell Biol 10 3125-3136 Willmann T, Beato M (1986) Steroid-free glucocorticoid receptor binds specifically to mouse mammary tumour virus DNA. Nature 324 688-691 Winkler H, Adam G, Mattes E, Schanz M, Hartig A, Ruis H (1988) Co-ordinate control of synthesis of mitochondrial and non-mitochondrial hemoproteins a binding site for the HAP-1 (CYPl) protein in the UAS region of the yeast catalase T gene. EMBO J 7 1799-1804... 

THY-R, thyroid hormone receptor TIMP, tissue inhibitor of metalloprotease TK, tyrosine kinase TLC, thin layer chromatography TLRs, Toll-like receptors TMAOX, trimethylamine oxidase TMY tobacco mosaic virus TNF, tumour necrosis factor TNF-a, tumour necrosis factor-a TNF-a-RTK, tumour necrosis factor-a receptor tyrosine kinase TOPI, DNA topoisomerase I TOPII, DNA topoisomerase II t-PA, tissue plasminogen activator TPA, 12-Tetradecanoylphorbol 13-acetate... 

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