P53/MDM

Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoreg-ulatory feedback loop. Genes Dev. 1993 7 1126-1132. 

MDM-2 Loss of p53 binding domain Cancer Tissue Sigalas et al. (1996)... 

Finlay, C. A., The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth. Mol Cell Biol, 1993, 13(1), 301-6. 

Momand, j., et ah. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell, 1992, 69(7), 1237-45. 

Lopez-Borges S, Lazo PA (2000) The human vaccinia-related kinase 1 (VRKl) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein. Oncogene 19(32) 3656-3664... 

The MDM2 protein is recognized as another important control element of p53 function. The MDM protein was first identified as an oncoprotein that negatively regulates p53 function. The regulatory function is performed within a network that includes the inhibitor pl9 (Fig. 14.10). 

Rg. 13.8 When damaged DNA is sensed, the Mdm-2 proteins receive a signal from a DNA-dependent protein kinase. DNA[Pg.241]

Recently, Mendoza et al. [227] focused on the molecular pathways governing apoptosis and summarized recent peptide-based approaches that target mdm-2, p53, NF-kB, ErbB2, MAPK, as well as Smac/DIABLO, lAP BIR domains, and Bcl-2 interaction domains, particularly BH3. A special attention was given to the anti-cancer effect of proteasome inhibitors (PI). 

Three peptides from the mdm-2 binding domain of human p53, residues 12-26 (PPLSQETFSDLWKLL), residues 12-20, and 17-26 were synthesized and attached at the carboxyl termini to the penetratin sequence, KKWKMRRNQFWVKVQRG. All three peptides were cytotoxic to human cancer cells in culture but not to... 

These peptides were cytotoxic in p53-null cancer cells or in those having mutant or normal p53 [235]. In another study, a GST fusion peptide with the sequence MPRFMDYWEGLN was introduced into osteosarcoma cells that overexpressed mdm-2, and in other cell lines that expressed mdm-2 and p53 but were transformed by the HPV16 E6 oncogene [236]. This peptide also induced apoptosis in p5 3-containing cells, but not in cells with homozygous deletions of p53. 

Blom R, Guerrieri C, Stal O, et al. Leiomyosarcoma of the uterus A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases. Gynecol Oncol. 1998 68 54-61. 

Lin J, Chen J, Elenbaas B, Levine AJ (1994) Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev 8 1235-1246... 

For explanation, see text. Identical factors may be listed in Tables I and II, as for example 14-3-3o and mdm-2. Both genes are transactivated by p53 but their products also bind p53 and regulate its activity. 

Mdm-2 Oncogene Transcriptional activation Repression of p53 Juven etal. (1993)... 

Fig. 2 A three-step model of p53 activation by stress signals. Activation of p53 requires covalent and noncovalent modifications in distinct domains of the protein. The first step involves phosphorylation in the N terminus, dissociation of complexes with mdm-2, and binding of histone-acetyl-transferases of the CBP/p300 family. The second step consists of coordinated modifications of the C terminus, including acetylation, changes in phosphorylation, and binding of specific proteins such as 14-3-3cr. The third step concerns the central portion of the protein and involves reduction of cysteines that play an important role in the conformation of the DNA-binding domain. For explanations and references, see text.

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