BIOCHEMISTRY - L. Stryer - 1984

VOLUME 3

Part IV INFORMATION

CHAPTER 30. VIRUSES

30.21. The src Gene Product of Avian Sarcoma Virus Is a Kinase Involved in Transformation

The Study of certain Temperature-sensitive mutants has yielded new insights into The Mechanism of transformation by avian Sarcoma virus. At high temperatures, these mutants multiply normally and fail to transform host Cells, whereas at low temperatures both processes proceed normally. Furthermore, fibroblasts transformed by these mutants at low temperatures revert to a normal phenotype when the temperature is raised. This shift from the transformed state to the normal one is completely reversible. Analysis of these mutants has shown that only a single viral protein—the product of the src Gene—is involved in the transformation process. The src gene was so named because it is capable of directing the synthesis of a protein that induces sarcomas. It is important to emphasize that in such mutant cells at high temperatures, the viral DΝA remains integrated with the cellular genome. Consequently, integration by itself does not lead to transformation; the rsc gene must be expressed for this to occur.

Class="center">Fig. 30.39. Electron micrograph of avian myeloblastosis virus particles. Introduction of this tumor-causing, RΝA-containing virus into newborn chicks induces malignant leukemia within 3 weeks

What is The Nature of the src gene product? Recent studies have shown that this 60-kDa protein is a protein-phosphorylating kinase. Research into the targets of this kinase is currently underway and will help elucidate the mechanism of transformation. It is remarkable that a single small protein can completely alter the growth pattern of a Cell and render it cancerous.

30.22. Double-Stranded RΝA Inhibits Protein Synthesis in Interferon-Treated Cells

The resistance of animal cells to many Viruses is significantly enhanced by interferons—a group of small Proteins synthesized and secreted by vertebrate cells infected with a virus. Double-stranded RΝA molecules exert a stimulating effect on interferon production. Interferons bind to The Plasma Membrane of other cells in the Organism and enhance their ability to resist viral infection, rendering the cells resistant to a broad spectrum of viruses. In contrast, antibody-mediated Immunity is highly specific. Interferons exhibit extremely high activity: as little as 10^-1 M is sufficient to produce a pronounced antiviral effect.

Interferon increases the antiviral resistance of cells by upregulating the synthesis of three Enzymes: oligonucleotide synthetase, endonuclease, and kinase. Until a sensitized cell is infected with a virus or exposed to double-stranded RΝA, these three enzymes remain inactive. Their activation blocks Protein Synthesis via two distinct pathways (Fig. 30.40). Protein kinase phosphorylates one of the protein synthesis initiation factors, thereby inactivating it. Recall that this same initiation factor serves as a target for the regulatory cascade in reticulocytes (Section 29.27). Another important consequence of the action of double-stranded RΝA on interferon-sensitized cells is The stimulation of mRΝA degradation. The endonuclease is activated by an oligoadenylate designated as 2',5'-A. Double-stranded RΝA stimulates the synthetase that produces this endonuclease activator. It would be extremely interesting to determine whether these regulatory pathways play any role in uninfected cells, aside from protecting them against viruses.

Fig. 30.40. Double-stranded RΝA stimulates mRΝA Cleavage (A) and inhibits the initiation of Protein synthesis in interferon-treated cells (B)