Nur77, also called TR3 or NGFI-B, is an immediate-early response gene and an orphan member of the steroid/thyroid/retinoid receptor superfamily. Nur77 exerts not only survival but also apoptotic effects in cells in response to different stimuli. We previously demonstrated that Nur77 in response to certain apoptotic stimuli could migrate from the nucleus to the cytoplasm, where it targets mitochondria through its interaction with Bcl-2. Nur77 interaction with Bcl-2 induces a Bcl-2 conformational change, resulting in conversion of Bcl-2 from an anti-apoptotic to a pro-apoptotic molecule. Our recent investigation of Nur77- Bcl-2 interaction revealed an unexpected protein-protein interaction site in the natively unstructured loop of Bcl-2, which differs from the classical BH3-binding groove known to be responsible for interaction of Bcl-2 with other Bcl-2 family members. Thus, we hypothesize that Bcl-2 conformational change is an important mechanism governing the survival and death of cells and it is an attractive target for drug development. In the proposed studies, we plan:
Aim 1. To characterize the Bcl-2 loop binding site and its regulation by phosphorylation.
Aim 2. To determine the role of growth factor survival signaling in the regulation of Bcl-2 conversion.
Aim 3. To identify small molecule Bcl-2 converters.
Aim 4. To study the therapeutic effects of Bcl-2 converters. Results obtained from these studies will enhance our understanding of the molecular mechanism of Bcl-2 conversion and regulation and may lead to identification of new strategies and agents for cancer therapy.

Public Health Relevance

We recently discovered that Bcl-2 can be converted from an anti-apoptotic to a pro-apoptotic molecule by nuclear receptor Nur77 through their interaction mediated by a new binding site in the loop of Bcl-2. We propose here to study the molecular mechanism by which Nur77 interacts with anti-apoptotic Bcl-2 family members and the functional consequences of the interaction. In addition, we plan to explore the therapeutic potential of Bcl-2 conversion. Our proposed studies are anticipated to provide important mechanistic insight into Bcl-2 conversion and to identify new small molecule Bcl-2 converters, which could find broad applicability to treating human cancers and other diseases characterized by elevated levels of Bcl-2.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089927-04
Application #
8514633
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2010-08-20
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$353,958
Indirect Cost
$172,441
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Zeng, Zhiping; Sun, Zhe; Huang, Mingfeng et al. (2015) Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB. Cancer Res 75:2049-60
Zhang, Xiao-kun; Su, Ying; Chen, Liqun et al. (2015) Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites. Acta Pharmacol Sin 36:102-12
Chen, Liqun; Wang, Zhi-Gang; Aleshin, Alexander E et al. (2014) Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site. Chem Biol 21:596-607
Zhou, Yuqi; Zhao, Wei; Xie, Guobin et al. (2014) Induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38 MAPK. Carcinogenesis 35:2660-9
Wang, Guang-Hui; Jiang, Fu-Quan; Duan, Ying-Hui et al. (2013) Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis. Cancer Res 73:307-18
Gao, Weiwei; Liu, Jie; Hu, Mengjie et al. (2013) Regulation of proteolytic cleavage of retinoid X receptor-α by GSK-3β. Carcinogenesis 34:1208-15
Wang, Zhi-Gang; Chen, Liqun; Chen, Jiebo et al. (2013) Synthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation. Eur J Med Chem 62:632-48
Sun, Z; Cao, X; Jiang, M-M et al. (2012) Inhibition of β-catenin signaling by nongenomic action of orphan nuclear receptor Nur77. Oncogene 31:2653-67

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