P53 gene

Alterations to the P53 gene are the most common genetic defects known in cancer [5]. The protein product of P53 is involved in a number of pathways that directly and indirectly lead to apoptosis. Many genes that are involved in apoptosis can be induced by this protein, which is a transcriptional transactivator. The emerging hypothesis is that p53 is a central node of a complex apoptotic network that may function differ ently in diver se cell types and tissues. For example, Bax, the prototype proapoptotic member of the Bcl2 family, can be transcriptionally induced by p53 in certain, but not all, cell types. Like p53, Bax can modulate the extent to which cells are sensitive to apoptosis caused by therapeutic agents. 

Behn M., Schuermann M. Sensitive detection of p53 gene mutations by a mutant-enriched PCR-SSCP technique. Nucleic Acids Res. 1998 26 1356-1358. 

An alternative anti-cancer strategy entails insertion of a copy of a tumour suppresser gene into cancer cells. For example, a dehciency in one such gene product, p53, has been directly implicated in the development of various human cancers. It has been shown in vitro that insertion of a p53 gene in some p53-dehcient tumour cell lines induces the death of such cells. A potential weakness of such an approach, however, is that 100 per cent of the transformed cells would have to be successfully treated to fully cure the cancer. Tumour suppressor-based gene therapy in combination with conventional approaches (chemotherapy or radiotherapy) may, therefore, prove most efficacious, and the sole gene-therapy-based medicine approved to date (in China only) is based upon this approach (Box 14.2). 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

Zhou, H. R. and Pestka J.J. Deoxynivalenol-induced apoptosis mediated by p38 MAPK-dependent p53 gene induction in RAW 264.7 macrophages. The Toxicologist 72, 330, 2003. 

B5. Berg, C., Hedrum, A., Holmberg, A., Ponten, F., Uhler, M. et al., Direct solid-phase sequence analysis of the human p53 gene by use of multiplex polymerase chain reaction and alpha-thiotriphosphate nucleotides. Clin. Chem. (Winston-Salem, N.C.) 41, 1461-1466 (1995). 

Sidransky, D., Eschenbach, A. V., Tsai, Y. C., Jones, P., Summerhayes, I. etal.. Identification of p53 gene mutations in bladder cancers and urine samples. Science 252, 706-709 (1991). 

As with c-erbB, overexpression of the suppressor p53 gene product has been found in different cancers (H3). Initially, it was believed that the detection of p53 protein in tumors meant the presence of a mutant gene product. However, we now know that normal p53 protein can be overexpressed in response to certain stimuli and stabilized by interaction with both cellular and viral proteins (H3). Irrespective of the mechanism giving rise to elevated protein levels, overexpression of p53 has been shown to be a prognostic marker in both breast and colorectal cancers (D8). In some studies, the presence of high levels of p53 has been shown to be a prognostic marker in axillary node-negative breast cancer patients (H3). 

Nigro, j. M., et ah. Mutations in the p53 gene occur in diverse human tumour types. Nature, 1989,... 

The p53 gene is a tumor suppressor gene, which means that its activity stops the formation of tumors via the production of p53 protein. As shown in the picture below, the p53 protein has four identical chains, which are joined together by a central tetramerization domain. The p53 protein molecule wraps around and binds DNA.This wrapping action then turns on another gene, which codes for a 21-kDa protein that regulates DNA synthesis. 

In October 2003, the SFDA approved the world s first gene therapy— Gendicine (a recombinant human adenovirus type 5 mediated delivery of p53 gene)— for the treatment of head and neck cancer. In 2005, another head and neck cancer drug, Oncorine (a recombinant oncolytic adenovirus type 5), was approved. In the same year, another recombinant human endostatin, Endostar, was approved for the treatment of small-cell lung cancer. 

The p53 gene encodes a protein that prevents a cell with damaged DNA from entering the S phase. Inactivation or deletion associated with Li Fraumeni syndrome and many solid tumors. 

Maesawa, C Tamura, G Suzuki, Y., Ishida, K., Saito, K., and Satodate, R. (1992) Sensitive detection of p53 gene mutations in esophageal endoscopic biopsy specimens by cell sorting combined with polymerase chain reaction single-strand conformation polymorphism analysis. Jpn. J. Cancer Res. 83, 1253-1256. 

Jenkins et alf" examined the formation of mutations in the p53 gene in oesophageal cell lines following treatment with deoxycholic acid for 24 h. The authors demonstrated an increased frequency of GC to AT mutations in KYSE-30 cells at neutral pH. The lARC TP53 Mutation Database compiles (http //www-p53.iarc.fr/index.html) p53 gene mutations identified in human... 

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