Abstract

The long-term objectives of this project are to determine the role of MDM2 oncogene in p21 regulation, to evaluate the potential of MDM2 and p21as novel targets for cancer chemoprevention and chemotherapy, and to translate these findings into more rational prevention and treatment of human cancers. The expression of p21 is under the control of p53. However, p21 is also regulated by p53-independent pathways. The MDM2 oncogene is overexpressed in many human cancers, with the MDM2 levels being associated with tumor progression and poor prognosis. MDM2 has a role in the regulation of p53 stability and activity. In addition, MDM2 also has p53-independent activity, which may be associated with its carcinogenic properties. Preliminary studies have indicated that MDM2 has an important role in regulation of p21. The inhibition of MDM2 with anti-MDM2 antisense oligonucleotide or siRNA targeting MDM2 significantly elevates p21 protein levels in cancer cells (p53 null). In contrast, overexpression of MDM2 diminishes the p21 level, shortening the p21 half-life. MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8-subunit. MDM2 functions as a negative regulator of p21, an effect independent of both p53 and ubiquitination. This application seeks to further clarify the role and mechanisms of MDM2 oncogene as a negative regulator of p21, including three Specific Aims: 1). To determine the mechanisms by which MDM2 regulates p21 at transcriptional level; 2) To determine the mechanisms by which MDM2 regulates p21 at post-translational level; and 3) To determine the in vitro and in vivo activity of MDM2 and p21 human cancer growth and progression. These studies will generate knowledge on the mechanisms responsible for the p53-independent carcinogenic activities of MDM2 and evaluate the potential of these pathways for human cancer prevention and treatment. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112029-02
Application #
6994432
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Perloff, Marjorie
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2006
Total Cost
$262,139
Indirect Cost

  Institution

Name
University of Alabama Birmingham
Department
Pharmacology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294

  Publications

Feng, Liang; Yao, Hang-Ping; Zhou, Yong-Qing et al. (2016) Biological evaluation of antibody-maytansinoid conjugates as a strategy of RON targeted drug delivery for treatment of non-small cell lung cancer. J Exp Clin Cancer Res 35:70
Qin, Jiang-Jiang; Wang, Wei; Voruganti, Sukesh et al. (2015) Inhibiting NFAT1 for breast cancer therapy: New insights into the mechanism of action of MDM2 inhibitor JapA. Oncotarget 6:33106-19
Yu, Jun-Xian; Voruganti, Sukesh; Li, Dan-Dan et al. (2015) Development and validation of an HPLC-MS/MS analytical method for quantitative analysis of TCBA-TPQ, a novel anticancer makaluvamine analog, and application in a pharmacokinetic study in rats. Chin J Nat Med 13:554-60
Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen (2015) Targeting the NF?B signaling pathways for breast cancer prevention and therapy. Curr Med Chem 22:264-89
Wang, Wei; Qin, Jiang-Jiang; Voruganti, Sukesh et al. (2015) Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications. Med Res Rev 35:1220-67
Wang, Wei; Nag, Subhasree; Zhang, Xu et al. (2015) Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications. Med Res Rev 35:225-85
Feng, Liang; Wang, Wei; Yao, Hang-Ping et al. (2015) Human tumor xenografts in mouse as a model for evaluating therapeutic efficacy of monoclonal antibodies or antibody-drug conjugate targeting receptor tyrosine kinases. Methods Mol Biol 1233:151-9
Voruganti, Sukesh; Qin, Jiang-Jiang; Sarkar, Sushanta et al. (2015) Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action. Oncotarget 6:21379-94
Sharma, Sharad; Yao, Hang-Ping; Zhou, Yong-Qing et al. (2014) Prevention of BMS-777607-induced polyploidy/senescence by mTOR inhibitor AZD8055 sensitizes breast cancer cells to cytotoxic chemotherapeutics. Mol Oncol 8:469-82
Zeng, Jun-Ying; Sharma, Sharad; Zhou, Yong-Qing et al. (2014) Synergistic activities of MET/RON inhibitor BMS-777607 and mTOR inhibitor AZD8055 to polyploid cells derived from pancreatic cancer and cancer stem cells. Mol Cancer Ther 13:37-48

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