The RNA viruses may be classified in two groups with respect to their tumorigenicity. (i) Non-defective viruses.
These viruses cause tumour formation, not due to an individual oncogene, but due to its ability to activate a cellular gene(s); two classic models are FeLV (Feline leukemia virus; Feline = of cats) and MMTV (mouse mammary tumour virus), (ii) Acute transforming viruses.
These viruses, each possesses an oncogene (absent in the ancestral virus, but derived later from host cell due to a transducing agent), which induces tumour formation in vivo
rather rapidly, and transforms cultured cells in vitro.
These transforming viruses are classified further according to the type of tumour, which is caused (e.g. leukemia, sarcoma, carcinoma, etc.), and the type of tumour is dependent on the oncogene, a virus carries. Oncogenes of some retroviruses are listed in Table 45.2. These oncogenes are related to some sequences in the cellular genome, called proto-oncogenes,
which are not oncogenic, but can give rise to an oncogene, particularly when captured by a retrovirus. The viral oncogenes and cellular proto-oncogenes are distinguished by using prefixes v
so that an oncogene carried by Rous Sarcoma Virus is called v-src
and the related proto-oncogene in the cellular genome is called c-src. v-onc
is actually derived from m-RNA, so that it contains uninterrupted sequence (or sequence missing at one or both ends), while the corresponding c-onc
may be a split gene with exons and introns. The mos, ras, sis
genes have been derived from entire c-onc
genes having no missing regions (Table 45.3). A v-onc
sequence is often expressed as a part of a fusion product, where the boundaries can be defined by comparing with the corresponding c-onc.
Several such examples include gab-abl (from v-abl
gag-fps (from v-fps
)and gag-fos (from v-fos
) (see Table 45.4).
|Fig. 45.1. Response of permissive cells and non-permissive cells to virus infection; permissive cells are productively infected by DN A tumour virus, which leads to lysis, but non-permissive cells get transformed through change in their phenotype.
|Fig. 45.2. Horizontal and vertical transfer of genetic information from retroviruses; horizontal transfer involves infection of new host, while vertical transfer involves transfer from one generation to the next generation, after integration of viral genome in the germ line of the host.
Atleast 20 c-onc
genes have been identified by their representation in retroviruses. Same c-onc
gene may be found in more than one retroviruses and more than one c-onc
gene may be present in different strains of the same retrovirus, although the different v-onc
genes may also be related (derived from different members of same c-onc
gene family^ e.g. c-ras
genes or c-myc
A wide variety of mechanisms that activate proto-oncogenes (c-onc
)are listed in Table 45.3.
That the v-onc
sequence is actually responsible for oncogenic potential of a transforming virus, has been proved by using following two approaches : (i) v-onc
genes could be mutated to abolish its transforming activity; (ii) c-onc
proto-oncogenes can be altered to become oncogenic. Changes in protein sequence of the product derived from c-onc,
relative to that derived from v-onc
is not always necessary for oncogenicity. In some cases, mere over-expression or altered regulation may lead to oncogenic phenotype.