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.
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.
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