- Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Genes and Cancer - 1. Three classes of genes are mutated frequently in cancer:
- a. Proto-oncogenes, whose products normally stimulate cell proliferation.
- b. Tumor suppressor genes, whose products normally inhibit proliferation.
- c. Mutator genes, whose products ensure accurate replication and maintenance of the genome.
Oncogenes - 1. Tumor viruses induce infected cells to proliferate and produce a tumor. There are two types, based on the viral genome:
- a. RNA tumor viruses transform cells by introducing viral oncogenes. (An oncogene is any gene that stimulates unregulated proliferation.)
- b. DNA tumor viruses do not carry oncogenes, and use other mechanisms to transform the cell.
Retroviruses and Oncogenes - 1. RNA tumor viruses are all retroviruses, and their oncogenes are altered forms of normal host genes. Examples include:
- a. Rous sarcoma virus.
- b. Feline leukemia virus.
- c. Mouse mammary tumor virus.
- d. Human immunodeficiency virus (HIV-1, cause of AIDS).
- 2. Structurally, retroviruses have:
- a. Two copies of the 7-10 kb ssRNA genome.
- b. A protein core (often icosahedral).
- c. An envelope derived from host membrane and bearing viral glycoproteins used to enter a host cell.
- 3. The retroviral life cycle was first characterized (1910) for a “filterable agent” from a chicken tumor, later named the Rous sarcoma virus (RSV). RSV’s genome organization is known (Figure 18.6).
- Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Fig. 18.6 The Rous sarcoma virus (RSV) RNA genome and the integration of the proviral DNA into the host (chicken) chromosome - Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
- 4. Upon retroviral infection, the ssRNA genome is released from the virus particle, and reverse transcribed to dsDNA (proviral DNA) by reverse transcriptase carried in the virus particle.
- a. Proviral DNA integrates into host chromosome:
- i. The 5’ (left) end of the viral genome has sequences R and U5, while the 3’ (right) end has sequences U3 and R.
- ii. During proviral synthesis, genome ends are duplicated to produce long repeats (LTR) of U3-R-U5. The LTRs contain transcription regulatory signals for viral genes (Figure 18.7)
- iii. Proviral DNA is ligated to produce a circular dsDNA with two adjacent LTRs.
- iv. Staggered nicks in proviral and host DNA are used for integration of the viral genome into the host chromosome.
- v. Single-stranded gaps are filled, producing short, direct repeats in host DNA flanking the provirus.
- b. Host RNA polymerase II transcribes the proviral DNA, and viral mRNAs are produced by alternative splicing. Three genes are characteristic of retroviruses:
- i. The gag (group antigen) gene encodes a precursor protein that is cleaved to form the protein core (capsid).
- ii. The pol (polymerase) gene produces a precursor protein cleaved to make reverse transcriptase and an enzyme for proviral integration.
- iii. The env (envelope) gene encodes the envelope glycoprotein, used to infect a host cell.
- 5. Oncogenic retroviruses carry an oncogene that is not involved in the cell cycle.
- a. Different retroviruses carry different oncogenes. In RSV the oncogene is src.
- b. Most retroviruses cannot replicate due to missing life-cycle genes (RSV is an exception).
- c. Retroviruses without oncogenes (nononcogenic retroviruses) direct their own life cycle, and do not change the growth properties of infected cells.
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