Transcription factor proto-oncogenes

Transcription factor proto-oncogenes that are silent or expressed at low levels in the progenitor cell are activated when placed imder control of potent enhancer elements of genes, which are normally highly expressed. 

Ras, when active, activates the serine/threonine kinase Raf (a MAP kinase kinase kinase), which activates MEK (a MAP kinase kinase), which activates MAP kinase (Fig. 18.5). Activation of MAP kinase results in the phosphorylation of cytoplasmic and nuclear proteins, followed by increased transcription of the transcription factor proto-oncogenes myc and fos (see below). Note that mutations in the genes for any of the proteins that regulate MAP kinase activity, as well as those proteins induced by MAP kinase activation, can lead to uncontrolled cell proliferation. 

Jin P, Ringertz NR (1990) Cadmium induces transcription of proto-oncogenes c-jun and c-myc in rat L6 myoblasts. J Biol Chem 265 14061-14064 Jin P, Sejersen T, Ringertz NR (1991) Recombinant platelet-derived growth factor-BB stimulates growth and inhibits differentiation of rat L6 myoblasts. J Biol Chem 266 1245-1249... 

A considerable number of transcription factors have reactive cysteine residues, which enable them to respond to the redox conditions in the cell. Since cadmium perturbs redox homeostasis, it can affect this class of transcription factors. If cadmium can displace the tetra-coordinate zinc atoms in zinc finger-containing transcription factors, it will affect them as well. Many of the pathways involving activation and inactivation of transcription factors involve kinases and phosphatases, themselves under the intricate control of calcium fluxes. It is therefore no surprise that cadmium will exert effects on the activity of transcription factors, the activation of proto-oncogenes, and thereby on gene expression (Figure 20.8i and i ). 

The protein Ras encoded by the ras proto-oncogene is, as we have seen, a signal transmission element. Mutant Ras, in which Gly is converted to any other amino acid, is always on and there is too much transmission of the growth factor signal to transcription factors. 

Finally, inappropriate expression of nuclear transcription factors can lead to cell transformation. For example, the products of he,fos and myc proto-oncogenes are transcription factors that regulate the expression of proteins that promote progression through the cell cycle. Levels of the Fos and Myc proteins are tightly regulated in normal cells. Uncontrolled expression of these proteins leads to cell proliferation. 

A large number of proto-oncogenes code for transcription factors required for progression of the cell cycle and/or for the differentiation of the cell. The best known and investigated examples of oncogenic mutated transcription factors involve the jun, fos and myc genes and the genes for the T3 receptor and the vitamin A acid receptor. 

Transcription factors. The proto-oncogenes c-mt/c447 451a, c-myb,452 454 c-fos, c-jun and c-efs455 all encode nuclear proteins involved in regulation of transcription. The 39 kDa protein Jim, which is encoded by c-jun, is a major component of the transcriptional activator called AP-1.456 459 It binds to palindromic enhancer sites (Chapter 28) in DNA promoters to increase the transcription rate for a group of genes. 

Margolis B, Hu P, Katzav S, Li W, Olivhi JM, Ullrich A, Weiss A, Schlessingsi J. Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs Nature 356 71-74,1992. 

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