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raf

the oncogene raf encodes three serine and threonine-specific protein kinases, called raf1 (c-raf), A-raf (or rafA) and B-raf (or rafB) that are localized in the cytoplasm.

c-raf1 is the cellular homolog of v-raf, an oncogene found in the acute transforming replication- defective type C murine sarcoma virus 3661. The mil oncogene, a second oncogene in the avian retrovirus MH2, which contains the myc oncogene, is the avian equivalent of the murine raf oncogene. The raf1 gene maps to human chromosome 3p25; raf2 is a processed pseudogene on human chromosome 4pter-p15.

raf1 is a protein of 70-75 kDa that is expressed in all organs and cell lines. rafA and rafB are expressed in urogenital tissues and brain, respectively.

Activated raf1 expresses a constitutive protein kinase and functions as an intracellular activator of cell growth. A revertant cell line, generated from v-raf-transformed 3T3 fibroblasts has been found to be deficient in the induction of early response gene by serum and Phorbol esters. This oncogene is important, therefore, for the regulation of some responses mediated by these stimuli.

Several cytokines have been shown to induce the synthesis of raf1 kinase, including PDGF, M-CSF, GM-CSF, EGF, IL2 and IL3. The activation of raf kinase, for example by the protein kinase activity of the intracellular domain of the EGF receptor eventually activates the transcription of genes, among them also cytokine genes with promoters that contain the binding site for transcription factor AP-1/PEA3 (see: jun).

An activated raf gene has been identified in the stomach cancer of a Japanese patient and there is some evidence for a relationship of raf1 to renal cell carcinoma. A radiation-resistant laryngeal carcinoma cell line has been shown also to contain altered raf1 sequences. The transforming DNA in a human glioblastoma line has been found to be identical with the raf gene.

TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES

raf1 functions have been inhibited by expressing c-raf1 antisense RNA or kinase-defective c-raf1 mutants (see also: Knock-out). Antisense RNA for c-raf1 interferes with proliferation of normal 3T3 fibroblasts and reverts raf-transformed cells. Inhibition of raf blocks proliferation and transformation by Ki-ras and Ha-ras.

See REFERENCES for entry raf

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