Mutations oncogenic

Behn M., Thiede C., Neubauer A., Pankow W., Schuermann M. Facilitated detection of oncogene mutations from exfoliated tissue material by a PNA-mediated enriched PCR protocol. J. Pathol. 2000 190 69-75. 

Oncogenic mutations P21 (ros) Colon, lung, breast, bladder tumors... 

Tumor cells differ from normal cells in one dramatic way they have lost the susceptibility to normal controls on cell proliferation. It should not surprise us then to learn that tumor suppressor genes and proto-oncogenes fall into one of three key categories. First, some oncogenic mutations directly affect cell proliferation. Second, other oncogenic mutations lead to loss of cell cycle control. Third, still other oncogenic mutations lead to genomic instability. 

Nomoto S, et al. Chnical application of K-ras oncogene mutations in pancreatic carcinoma detection of micrometastases. Semin Surg Oncol 1998 15(l) 40-46. 

How does the occurrence of oncogenic mutations favored at particular positions fit into the structural picture of the Ras function ... 

The observation that position 61 - after position 12 - is the second most frequent site of oncogenic mutations in solid tumors is in agreement with the central importance of Gtn61 for GTP hydrolysis. Ghi61 is a highly conserved amino acid within the superfamily of GTPases a Ghi residue in an equivalent position is also found in the a-subimits of heterotrimeric GTPases (see 5.5.6 and Fig. 5.18). Exceptions include the bacterial... 

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). 

The activity of Ser/Thr-specific protein kinases is often controlled by autoinhibitory sequences (see 7.1.5). Loss or lack of function of autoregulatory sequences due to an oncogenic mutation can remove Ser/Hir kinase activity bound into mitogenic signaling pathways from normal control and thereby promote tumors. An example is the Raf kinase (see 9.6). Viral v-Raf oncoproteins are characterized by a deletion of the NH2-terminal regulatory sequences. 

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. 

Fig. 14.8. DNA binding domain of the tnmor suppressor protein p53 in complex with DNA. Crystal structure of the core domain of p53 (amino acids 102-292) in complex with a double-stranded DNA that contains a specific binding site for p53 (Cho et al., 1994). The amino acid positions are highhghted at which frequent oncogenic mutations are observed (see Fig. 14.9). MOLSKRIPT representation according to Krauhs, (1991).

Another gene controlled by p53 is the gene for the Bax protein (Miyashita and Reed, 1995). The Bax protein has an activating function in the initiation of apoptosis. Activation of the p53 protein due to DNA damage can initiate the apoptotic program via stimulation of bax transcription (see Chapter 15). If the transcription regulating function of p53 is lost due to an oncogenic mutation, this apoptotic path caimot be initiated. 

Martinez LA, Naguibneva I, Lehrmann H, Vervisch A, Tchenio T, Lozano G, Harel-Bellan A (2002) Synthetic small inhibiting RNAs efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc Natl Acad Sci USA 99 14849-14854... 

Proliferative genes are proto-oncogenes mutated proto-oncogenes may become oncogenes. 

Also T. Attie, A. Pelet, P. Edery, C. Eng, L. M. Mulligan, J. Amiel, et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet, 4 (8), 1381-1386, 1995. 

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