Bcl-2 function on the endoplasmic reticulum

Bcl-2 在内质网上的功能

• 批准号: 8596796
• 负责人: CLARK W DISTELHORST
• 金额: $ 27.59万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8596796
• 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)：通过抑制细胞凋亡，Bcl2蛋白对肿瘤的发生和固有的癌症治疗耐药都有贡献。这项拨款支持的研究正在研究Bcl2的S作用机制的一个特殊方面，即抑制促进细胞凋亡的钙信号。我们发现，Bcl2与内质网(ER)上的三磷酸肌醇受体(IP3R)相互作用，从而抑制IP3诱导的钙升高。在当前的资助期间，我们使用FRET演示了这种相互作用在细胞中的作用，并绘制了Bcl-2和IP3R上的相互作用位点。基于这一信息，我们开发了一种抑制Bcl-2-IP3R相互作用的多肽，多肽2。当这种多肽被输送到细胞内时，可以逆转Bcl2对促凋亡钙信号的抑制，并触发长时间的钙振荡，从而提高促凋亡蛋白Bim。本研究通过研究Bcl2-IP3R相互作用调节IP3R通道活性从而抑制依赖于IP3的钙升高的基本机制来继续这项工作。此外，本研究还探讨了多肽2抑制Bc l-2-IP3R相互作用触发钙振荡和增加Bim水平的机制。最后，这项建议探索了靶向Bcl2-IP3R相互作用的概念，以与其他治疗药物协同治疗Bcl2过表达的癌症，包括慢性淋巴细胞性白血病。

项目成果

IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2.

• DOI: 10.1038/cddis.2013.140
• 发表时间: 2013-05-16
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Akl H;Monaco G;La Rovere R;Welkenhuyzen K;Kiviluoto S;Vervliet T;Molgó J;Distelhorst CW;Missiaen L;Mikoshiba K;Parys JB;De Smedt H;Bultynck G
• 通讯作者: Bultynck G

Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl.

• DOI: 10.1038/cdd.2011.97
• 发表时间: 2012-02
• 期刊: Cell death and differentiation
• 影响因子: 12.4