Oncogene stability

This model was developed at CIEA in Japan, and the first information about the mouse was published in 1990. The mice have five or six copies of the human H-ras proto-oncogene inserted in tandem into their genome surrounded by their own promoter and enhancer regions. This transgene has been very stabile, with no loss of responsiveness since the model was developed. The transgene codes for a molecular switch protein in the same way as the previous model, but the transgene is expressed in all organs and tissues. Thus the response endpoint is not primarily dermal. 

Apart from telomeres, G-quadruplexes are also present in the upstream promoter regions of certain oncogenes. G-quadruplex targeted molecules may interact at these sites as well. In fact, the cationic prophyrin, TMPyP4 and the core modified expanded prophyrin analogue 5,10,15,20-[tetra(N-methyl-3-pyridyl)]-26,28-diselenasapphyrin chloride (Se2SAP) have been found to cause repression of transcriptional activation of c-MYC in cells by G-quadruplex stabilization (Seenisamy et al, 2005). 

Tauchi H, Matsuura S, Kobayashi J, Sakamoto S, Komatsu K (2002) Nijmegen breakage syndrome gene, NBSl, molecular links to factors for genome stability. Oncogene 21(58) 8967—8980 Taylor SS (1982) The in vitro phosphorylation of chromatin by die catalytic subunit of cAMP-dependent... 

Blattner C, Tobiasch E, Litfen M, Rahmsdorf HJ, Herrlich P (1999) DNA damage induced p53 stabilization no inchcation for an involvement of p53 phosphorylation. Oncogene 18 1723-1732... 

The effect of oncogenic mutations at position 61 can also be explained using the Ras-GAP complex. GIn61 has a central function in GTP hydrolysis in that it contacts and coordinates the hydrolytic water molecule and the O-atom of y-phosphate of GTP and thus stabilizes the transition state. Amino acids with other side chains apparently cannot fulfil this function, as shown by the oncogenic effect of Ghi61 mutants in which Ghi61 is replaced by other amino acids (other than Glu). 

A change in the gene expression or stability of a proto-oncogene product may lead to an increase in the cellular concentration of the protein. Due to the increased concentration, a mitogenic signal mediated by a proto-oncogene product may be amplified. 

Midgley, C.A. and Lane, D.P. (1997) P53 protein stability in tumor cells is not determined by mutation but is dependent on MDM2 binding. Oncogene, 15, 1179-1189. 

Suzuki, H., Yagi, K., Kondo, M., Kato, M., Miyazono, K., and Miyazawa, K. 2004. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements. Oncogene 23 5068-5076. 

The 3 UTR is defined as the mRNA sequences following the termination codon. The 3 UTR is thought to play a potential role in mRNA stability. AU-rich motifs are commonly found in the 3 UTR of mRNA of cytokines, growth factors and oncogenes. These motifs are mRNA instability elements and should be... 

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