Info

incubation period

in vitro Iransformation

No

No

Yes

" Except for Rous sarcoma virus

" Except for Rous sarcoma virus

B-cell, T-cell, or myeloid leukemia with low efficiency and after a much longer incubation period.

Replication of Retroviruses

The complete replication cycle of retroviruses is described in Chapter 35, but certain aspects associated with the integration of the DNA copy of the RNA genome into the ceiluiar DNA need to be described here in order to explain viral oncogenesis. When released in the cytoplasm, the ssRNA genome is converted to dsC>WA which is integrated into the chromosomal DNA as provi-rus (Fig 11-2A,B). The expression of mRNA from the provirus is under the control of the viral transcriptional regulatory sequences, which include promoter and enhancer elements, both of which are located in the bug terminal repeat (LTR) in other ways the proviral DNA behaves as do other chromosomal genes, segregating like other markers and being transmitted via the germ line. The strong promoter in the LTR influences the expression of genes in the vicinity of the insertion site, such that it may increase the expression of downstream cellular genes. Sometimes a cellular gene may be inactivated as a consequence of disruption at the point of insertion of the provirus, and the provirus may also acquire and transduce cellular genes.

Mechanisms of Tumor Production by Retroviruses

Retroviruses produce tumors in one of three ways: (1) the transducing retro-z>iriises introduce a v-oitc gene, which is controlled by viral regulatory sequences present in the LTR of the viral genome, into a chromosome of a normal ceil; (2) cis -activating retroviruses, which lack a v-onc gene, transform cells by integrating close to a c-ohc gene and thus usurping normal cellular regulation of this gene; and (3) trans-activating retroviruses contain a gene that codes for a regulatory protein which may either increase transcription from the viral LTR oi interfere with the transcriptional control of specific cellular genes.

Since most transducing retroviruses have lost part of their genome in the course of the original recombination event that led to the acquisition of a c-onc gene (now a v-onc gene), they are replication-defective and rely for their replication on a helper retrovirus which is always found with them in the animal and in most instances is their progenitor. Transducing retroviruses transform cells rapidly both in vitro and in vtvo. Whereas de activating retroviruses are replication-competent, induce tumors more slowly, and do not transform cells in culture, frans-activating retroviruses either have no oncogenic activity or induce tumors very late, by affecting cellular transcription.

Modes of Action of Transduced Retroviral Oncogenes

The "oncoprotein" products of all retroviral oncogenes appear to act either by interfering with signal transduction, that is, the transfer of signals from the membrane to the cell interior, or directly with the regulation of cellular genes. Although the complete pathway via which any given oncoprotein stimulates cell growth is not yet completely comprehended, there is some information on where they fit into (he overall picture of growth control of the cell (Fig. 11-3, Table 11-4).

Growth Factors

Only one example of an oncogene encoding a growth factor analog is known, v-sis, which codes for one of the two polypeptide chains of platelet-derived growth factor (PDGF). This retroviral v-onc gene, under the control of the powerful enhancer/promoter complex in the LTR, induces fibroblasts to manufacture growth factor, which they do not normally express, leading to immortalization of fibroblasts in culture and possibly the induction of malignant tumors.

Fig. 11-3 Cellular growth control involves tour types of proteins, the genes for which can give rise to oncogenes They are (1) growth factors, (II) receptors, (ill) intracellular transducers, and (IV) intranuclear factors See Table 11-4 for examples and text for explanation. (Modiiied from J E. Darnell, H Lodish, and D. Baltimore, "Molecular Cell Biology," 2nd Ed , p 985 Scientific American Books, New York, 1990.)

Fig. 11-3 Cellular growth control involves tour types of proteins, the genes for which can give rise to oncogenes They are (1) growth factors, (II) receptors, (ill) intracellular transducers, and (IV) intranuclear factors See Table 11-4 for examples and text for explanation. (Modiiied from J E. Darnell, H Lodish, and D. Baltimore, "Molecular Cell Biology," 2nd Ed , p 985 Scientific American Books, New York, 1990.)

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