Bcl-2 function on the endoplasmic reticulum

Bcl-2 在内质网上的功能

• 批准号: 8458912
• 负责人: CLARK W DISTELHORST
• 金额: $ 26.74万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-03 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458912
• 关键词: Antineoplastic Agents; Apoptosis; Apoptotic; BCL-2 Protein; BCL2 gene; Calcineurin; Calcium; Calcium Channel; Calcium Oscillations; Calcium Signaling; Calcium ion; Cell Death; Cells; Chronic Lymphocytic Leukemia; Docking; Endoplasmic Reticulum; Fluorescence Resonance Energy Transfer; Funding; Goals; Grant; ITPR1 gene; Inositol; Ions; Malignant Neoplasms; Maps; Mediating; Modification; Peptides; Phosphorylation; Process; Protein Isoforms; Protein Serine/Threonine Phosphatase; Proteins; Research; Research Support; Resistance; Ryanodine Receptor Calcium Release Channel; Site; Specificity; Testing; Therapeutic; Therapeutic Agents; Work; base; cancer cell; cancer therapy; inhibitor/antagonist; leukemia/lymphoma; mouse model; prevent; pro-apoptotic protein; public health relevance; receptor; synergism; therapy design; tool; tumorigenesis

DESCRIPTION (provided by applicant): The Bcl-2 protein contributes to both oncogenesis and intrinsic cancer treatment resistance by inhibiting apoptosis. Research supported by this grant is investigating one particular aspect of Bcl-2's mechanism of action, the inhibition of calcium signals that promote apoptosis. We discovered that Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (IP3R), an IP3-gated calcium channel on the endoplasmic reticulum (ER), thus inhibiting IP3-induced calcium elevation. In the current funding period we used FRET to demonstrate this interaction in cells and mapped the interaction sites on both Bcl-2 and the IP3R. Based on this information we developed a peptide inhibitor of Bcl-2-IP3R interaction, Peptide 2. This peptide, when delivered into cells, reverses the inhibition of pro-apoptotic calcium signals by Bcl-2 and triggers prolonged calcium oscillations that elevate the pro-apoptotic protein Bim. The present proposal continues this work by investigating the fundamental mechanism by which Bcl-2-IP3R interaction regulates IP3R channel activity and thus inhibits IP3- dependent calcium elevation. Also, this proposal investigates the mechanism by which Peptide 2-mediated inhibition of Bcl-2-IP3R interaction triggers calcium oscillations and increases Bim levels. Finally, this proposal explores the concept of targeting Bcl-2-IP3R interaction for treatment of Bcl-2 over-expressing cancers, including chronic lymphocytic leukemia, in synergy with other therapeutic agents.

描述（由申请人提供）：Bcl-2蛋白通过抑制细胞凋亡而促进肿瘤发生和内在癌症治疗性。该赠款支持的研究是研究BCL-2作用机理的一个特定方面，即抑制促进凋亡的钙信号。我们发现Bcl-2与肌醇1,4,5-三磷酸受体（IP3R）是内质网（ER）上的IP3门控钙通道（ER）相互作用，从而抑制IP3诱导的钙升高。在当前的资金期间，我们使用FRET来证明细胞中的这种相互作用，并在Bcl-2和IP3R上映射了相互作用位点。基于这些信息，我们开发了Bcl-2-IP3R相互作用，肽2的肽抑制剂。该肽在输送到细胞中时会逆转Bcl-2对促凋亡的钙信号的抑制，并触发延长钙的振​​荡，从而升高了pro-磷脂蛋白BIM。本提案通过研究Bcl-2-IP3R相互作用调节IP3R通道活性并因此抑制IP3依赖性钙升高的基本机制来继续这项工作。此外，该提案研究了肽2介导的BCl-2-IP3R相互作用抑制肽触发钙振荡并增加BIM水平的机制。最后，该提案探讨了针对Bcl-2-IP3R相互作用的概念，用于治疗BCL-2过表达的癌症，包括慢性淋巴细胞性白血病，以与其他治疗剂协同作用。