MDM2 and its homolog MDMX are both important binding partners and regulators of the p53 tumor suppressor. MDM2 is a p53-inducible ubiquitin E3 ligase that promotes p53 degradation, forming a negative feedback loop. The importance of MDM2 in regulating p53 stress response is well established. However, little is known about the regulation of MDMX and its role in signaling to p53. Knockout experiments showed that MDMX is essential for viability of wild type but not p53-null mouse embryos, indicating that it is an important inhibitor of p53. Therefore, signaling pathways to p53 are likely to target MDMX in order to achieve efficient control of p53. We recently found that DNA damage induces proteasome-mediated degradation of MDMX. MDM2 promotes ubiquitination and degradation of MDMX, suggesting that MDMX is regulated in part by MDM2. We have also identified casein kinase 1 alpha as an MDMX binding partner that enhances the ability of MDMX to inhibit p53. MDMX is often overexpressed in tumor cells containing wild type p53 through increased promoter activity. We hypothesize that signaling to p53 is in part mediated through regulation of MDMX at the level of ubiquitination, phosphorylation and transcription. We propose the following experiments to study the function and regulation of MDMX. (1) Determine the mechanism of p53 inhibition by MDMX. (2) Investigate the regulation of MDMX by ubiquitination and sumoylation. (3) Investigate the regulation of MDMX by phosphorylation. (4) Determine the mechanism of MDMX overexpression in tumor cells. These experiments should lead to a better understanding of the mechanisms that regulate MDMX and the role of MDMX in the p53 tumor suppressor pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109636-03
Application #
7096023
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Blair, Donald G
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$261,038
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Chen, Jiandong (2016) The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. Cold Spring Harb Perspect Med 6:a026104
Wei, Xi; Wu, Shaofang; Song, Tanjing et al. (2016) Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding. Proc Natl Acad Sci U S A 113:E2558-63
Sun, Lidong; Kokura, Kenji; Izumi, Victoria et al. (2015) MPP8 and SIRT1 crosstalk in E-cadherin gene silencing and epithelial-mesenchymal transition. EMBO Rep 16:689-99
Yang, Leixiang; Song, Tanjing; Chen, Lihong et al. (2015) Nucleolar repression facilitates initiation and maintenance of senescence. Cell Cycle 14:3613-23
Chen, Lihong; Borcherds, Wade; Wu, Shaofang et al. (2015) Autoinhibition of MDMX by intramolecular p53 mimicry. Proc Natl Acad Sci U S A 112:4624-9
Zheng, H; Chen, L; Pledger, W J et al. (2014) p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression. Oncogene 33:734-44
Cheng, Qian; Song, Tanjing; Chen, Lihong et al. (2014) Autoactivation of the MDM2 E3 ligase by intramolecular interaction. Mol Cell Biol 34:2800-10
Yang, Leixiang; Song, Tanjing; Chen, Lihong et al. (2013) Regulation of SirT1-nucleomethylin binding by rRNA coordinates ribosome biogenesis with nutrient availability. Mol Cell Biol 33:3835-48
Zheng, Hong; Yang, Leixiang; Peng, Lirong et al. (2013) hMOF acetylation of DBC1/CCAR2 prevents binding and inhibition of SirT1. Mol Cell Biol 33:4960-70

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