P53 tumor suppressor

Harris, C., Hollstein, M. Clinical implications of the p53 tumor-suppressor gene. N. Engl. f. Med. 

Jeffrey, P.D., Gorina, S., Pavletich, N.P. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 Angstroms. Science 267 1498-1502, 1995. 

Nucleic acids in the DNA contain a high number of nucleophilic sites that can be attacked by electrophilic intermediates (metabolites) of chemical compounds. DNA adducts formed may cause alterations in the expression of a critical gene in the cell and thus lead to cell death. For example, modification of p53 tumor suppressor gene may inactivate the functions of the p53 protein and render cells sensitive to malignant transformation. Also, formation of RNA adducts may inhibit key cellular events because RNA is essential for protein synthesis. 

MDM2 Protein antagonist of p53 tumor suppressor protein Sarcomas... 

TF transcription factor, R receptor, Fur ferric uptake regulation protein, NF-kB nuclear factor-kB, AP-1 activator protein-1, Egr-1 early growth response-1, VDR la,25-dihydroxy-vitamin D3 receptor, RXR retinoid X receptor, PPARy peroxisome proliferator-activated receptor y NFAT nuclear factor of activated T-cells, HSF heat shock factor, p53 tumor suppressor p53, HIF-1 hypoxia inducible factor-1. ... 

Chang, F., S. Syrjanen, K. Kurvinen, and K. Syrjanen. 1993. The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. Am J Gastroenterol 88(2) 174-86. 

The p53 molecule. (Source Goodsell DS.The Scripps Institute, Featured Molecule p53 Tumor Suppressor, Bio.Com. http //www.bio.com/ [accessed September 7, 2002].)... 

Park J, Wood M A, Cole MD (2002) BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol 22 1307-1316 Park JH, Roeder RG (2006) GAS41 Is Required for Repression of the p53 Tumor Suppressor Pathway... 

Currently, more than 400 human somatic cell gene therapy protocols are being tested. Most of these involve the use of genetically modified cells to treat noninherited diseases. For example, normal copies of the p53 tumor suppressor gene are inserted into lung tumors to halt tumor progression, and genetically modified cells have been used to create new coronary vessels in patients with coronary heart disease. Success has also been achieved in the treatment of hereditary disease (most notably, the recent successful treatment of X-linked severe combined immune deficiency see Clinical Correlate). 

Scoumanne, A. and Chen, X. (2008) Protein methylation a new mechanism of p53 tumor suppressor regulation. Histology and Histopathology, 23, 1143-1149. 

Crystal structure of a p53 tumor suppressor-DNA complex understanding tumorigenic mutations. Science 265,346-355. 

The mutation of the p53 tumor suppressor gene has been well recognized to be associated in most head and neck malignancies. ONYX-015 is an adenovirus vector com-... 

Bouvet M, Bold RJ, Lee J, et al. Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. AnnSurg Oncol 1998 5 681-688. 

The discovery of this family of E3 enzymes started from the studies on the targeted degradation of the p53 tumor suppressor protein. Ubiquitinylation and degradation of p53 can be mediated by the papillomavirus E6 oncoprotein (see below) in collaboration with a further protein, E6-AP (E6 associated protein). E6-AP was the first member of a large family of E3 enzymes, the Hect (homologous to E6-AP C-terminus ) domain family. These proteins contain an essential active site Cys residue near the C-terminus and one or several WW domains ( see Chapter 8.2.6). 

Fig. 13.10. Regulation and attack points of inhibitors of cyclin-dependent protein kinases (CKIs) in mammals. The various CKIs are activated and regulated by different signals. Inhibitory activity of the CKIs is specific for the different CDKs and CDK-cyclin combinations. p53 tumor suppressor protein p53 TGPP transforming growth factor P pRb tumor suppressor protein pRb p21 p2icipi. p27- pl6 pl6 ° CDK cyclin-dependent protein kinase Cyc cyclin E2F trans-...

Fig. 13.11. Substrates and phase-spedfic activation of CDKs in the ceU cycle. An overview is shown of the phase-specific activation of the most important CDK-cychn complexes and of selected substrates. The arrows indicate activation and phosphorylation. CDK cycMn-dependent protein kinase p53 tumor suppressor p53 pRb tumor suppressor pRb CDC25 CDC25 phosphatase TFIIIB transcription factor TFIIIB R restriction point.

Cho, Y, Gorina, S., Jeffrey, P.D. and Pavletich, N.P Crystal structure of a p53 tumor suppressor-DNA complex understandung tumorigenic mutations (1994) Science 265, 346-355... 

O Connor PM, Jackman J, Bae I et al. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anti-cancer drug screen and correlations with the growth-inhibitory potency of 123 anti-cancer agents. Cancer Res 1997 57 4285 300. 

Loss of the p53 tumor suppressor gene has been shown to impede the anti-leukemic response to BCR-ABLl inhibition (43). Another mechanism for resistance that is independent of BCR-ABLl and that has been demonstrated in vitro is over-expression of SRC-related kinases such as LYN (44). It appears that kinases from the SRC family mediate signaling of BCR-ABLL This has been demonstrated in vitro with the use of SRC kinase inhibitors and SRC mutants that are kinase defective (45,46,47). 

As well as apoptosis, the p53 tumor suppressor gene causes DNA repair, blocks angiogenesis, and causes cell cycle arrest. As with oncogenes, tumor suppressor genes also have effects on cell cycle control. 

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