The tumor suppressor p53 and the oncoprotein simian virus 40 T antigen bind to overlapping domains on the MDM2 protein.

Brown, Doris R.; Muñoz, Rubén M.; Subler, Mark A.; Deb, Sumitra

doi:10.1128/mcb.13.11.6849

Cited by 56 publications

(58 citation statements)

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“…The MDM2 protein is able to form a protein ± protein interaction with p53 which inactivates the transactivation function of p53 (Brown et al, 1993;Haines et al, 1994;Momand et al, 1992;Oliner et al, 1993;Wu et al, 1993) and also targets p53 for degradation (Haupt et al, 1997;Kubbutat et al, 1997). Overexpression of MDM2 can inhibit the ability of p53 to suppress transformation (Finlay, 1993) as well as inhibit the ability of p53 to evoke cell cycle arrest or induce apoptosis (Chen et al, 1996).…”

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confidence: 99%

p53 binds to a constitutively nucleosome free region of the mdm2 gene

1998

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The mdm2 oncogene is a p53 responsive gene which contains both a p53 independent and a p53 dependent promoter (P1 and P2 respectively). We have utilized ligation mediated PCR genomic footprinting in order to investigate the intra-nuclear binding of p53 to the mdm2 P2 promoter. The DNase I protection pattern in nuclei from murine cells lacking p53 has been compared to the protection pattern in cells containing a temperature sensitive p53-Val135. At 328C p53-Val135 assumes a wild-type conformation while at 378C this p53 is conformationally mutant. We observed clear wild-type p53 dependent protection of the putative p53 response elements (REs) as well as protection of the adjacent TATA box. Interestingly the protection pattern observed with puri®ed wild-type p53 on naked DNA showed less nucleotide sequence protection than the protection observed to be p53 dependent in nuclei. Constitutive DNase I hypersensitivity at both the mdm2 P1 and P2 promoters was detected by indirect Southern blot analysis. DNase I hypersensitivity re¯ects altered chromatin conformations resulting, most likely, from the absence of nucleosomes. Taken together our ®ndings suggest that the mdm2 P2 promoter is maintained in a nucleosome free state which is pre-primed for transcriptional activation by p53.

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confidence: 99%

p53 binds to a constitutively nucleosome free region of the mdm2 gene

1998

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“…Construction of plasmids expressing MDM2 has been described in detail (7,10). The deletion mutant MDM2 Del 491-110 was generated by PCR by using primers flanking initiation and termination codons and inserting a NheI linker with stop codons in all three reading frames.…”

Section: Plasmids and Mdm2 Deletion Mutantsmentioning

confidence: 99%

“…The deletion mutant MDM2 Del 491-110 was generated by PCR by using primers flanking initiation and termination codons and inserting a NheI linker with stop codons in all three reading frames. The mutant was cloned in pGEM3zf (−) vector, sequenced, and subcloned in pCMV plasmid (7,14) for in vivo expression.…”

Section: Plasmids and Mdm2 Deletion Mutantsmentioning

confidence: 99%

“…These interactions are considered to be possible mechanisms for the oncogenic function of MDM2 (1)(2)(3). MDM2 recognizes the transactivation domain of p53 and inactivates p53-mediated transcriptional activation (6)(7)(8)(9)(10). Work from our laboratory showed that this interaction is needed for the inhibition of p53-mediated transactivation (7,10).…”

Section: Introductionmentioning

confidence: 99%

“…MDM2 recognizes the transactivation domain of p53 and inactivates p53-mediated transcriptional activation (6)(7)(8)(9)(10). Work from our laboratory showed that this interaction is needed for the inhibition of p53-mediated transactivation (7,10). MDM2 also degrades p53 by targeting p53 for ubiquitination (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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MDM2 Controls the Timely Expression of Cyclin A to Regulate the Cell Cycle

Frum

Ramamoorthy

Mohanraj

et al. 2009

Molecular Cancer Research

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Overexpression of MDM2 has been related to oncogenesis. In this communication, we present evidence to show that MDM2 controls the cell cycle-dependent expression of cyclin A by using a pathway that ensures its timely expression. MDM2 does not inhibit cyclin D or E expression. Silencing of endogenous MDM2 expression elevates cyclin A expression. The p53-binding domain of MDM2 harbors a SWIB region homologous to a conserved domain of a chromosome remodeling factor BRG1-associated protein.The SWIB domain of MDM2 inhibits cyclin A expression in a p53-and BRG1-dependent fashion, suggesting that MDM2 interferes with p53 binding of the BRG1 complex freeing it to repress cyclin A expression. Silencing of cyclin-dependent kinase (cdk) inhibitor p16 prevents MDM2-mediated inhibition of cyclin A expression, implicating its role in the process. MDM2-mediated repression of cyclin A expression induces G 1 -S arrest, which can be rescued by ectopic expression of cyclin A. Cancer cells lacking p53, p16, or BRG1 escape MDM2-mediated repression of cyclin A expression and growth arrest. Our data propose a novel mechanism by which MDM2 controls the cell cycle in normal cells and how cancer cells may escape this important safety

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Expression profile of MDM-2 proteins in chronic lymphocytic leukemia and their clinical relevance

et al. 1997

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The MDM-2 oncoprotein exists in an autoregulatory feedback loop with the tumor suppressor protein p53. Therefore, intracellular levels of these two proteins may play important roles in cell proliferation and tumorigenesis. Several MDM-2 proteins (Mr 35-100 Kd) have been demonstrated in human cell lines. We report here the expression profile of MDM-2 and p53 proteins in 87 cases of chronic lymphocytic leukemia (CLL) as detected by immunoblot analysis. The MDM-2 proteins (p57, p59, p67, and p90) were found to be overexpressed in different combinations in 56/87 (64%) of cases of CLL when compared with normal volunteers. The MDM-2 protein p57 was predominantly overexpressed 46/87 (53%) in CLL. In 22/87 (25%) cases of CLL p57 was overexpressed alone, and in 24/87 (28%) cases it was co-overexpressed with other MDM-2 proteins p59/p67/p90. Six of the 87 cases of CLL showed overexpression of the tumor suppressor protein p53 by immunoblot analysis, and five of those cases also co-overexpress MDM-2 protein p57. No statistically significant correlation of MDM-2 protein overexpression to clinical disease stage and history of previous chemotherapy of CLL patients has been found. However, considering the oncogenic potential of overexpressed MDM-2 proteins, a possible role of MDM-2 proteins in the promotion of CLL disease remains to be evaluated.

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The tumor suppressor p53 and the oncoprotein simian virus 40 T antigen bind to overlapping domains on the MDM2 protein.

Abstract: The oncogene mdn2 has been found to be amplified in human sarcomas, and the gene product binds to the tumor suppressor p53. In

Cited by 56 publications

References 58 publications

p53 binds to a constitutively nucleosome free region of the mdm2 gene

p53 binds to a constitutively nucleosome free region of the mdm2 gene

MDM2 Controls the Timely Expression of Cyclin A to Regulate the Cell Cycle

Expression profile of MDM-2 proteins in chronic lymphocytic leukemia and their clinical relevance

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