P53-tumor-suppressor gene

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

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. 

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. 

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). 

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. 

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. 

Morrison R. S., Wenzel H. J., Kinoshita Y., Robbins C. A., Donehower L. A., and Schwartzkroin P. A. (1996). Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J. Neurosci. 16 1337-1345. 

Nielsen, L.L. and Maneval, D.C. (1998) p53 tumor suppressor gene therapy for cancer. Cancer Gene Ther., 5, 52-63. 

Several reports in the literature state that DOPE, while successfully used for in vitro gene delivery, is a poor helper lipid for in vivo applications [28-32], Instead, for reasons that are not understood, lipid mixtures for successful transfection in vivo seem to require cholesterol [33]. In fact, an equimolar mixture of cholesterol and DOTAP is widely used for in vivo experiments and clinical trials. Cholesterol has also been included in liposomes along with cationic DOTAP and fusogenic DOPE to form a potent mixture used to study the treatment of ovarian cancer by delivery of the p53 tumor suppressor gene [34, 35]. 

Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene clues to cancer etiology and molecular pathogenesis. Cancer Res 1994 54 4855-4878. 

Alterations of various cell signaling pathways can result in dysregulation of apoptosis and lead to cancer. The p53 tumor suppressor gene is a transcription factor that regulates the cell cycle and is the most widely mutated gene in human... 

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