Pro-apoptotic BID in DNA Damage and Leukemogenesis

DNA 损伤和白血病发生中的促凋亡 BID

• 批准号: 7246734
• 负责人: Sandra S Zinkel
• 金额: $ 38.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246734
• 关键词: Pro; apoptotic; BID; DNA; Damage

DESCRIPTION (provided by applicant): The Bcl-2 family constitutes a crucial checkpoint in the cell death pathway. BID is a member of the "BH3- only" subset of this family and requires its conserved BH3 domain for its pro-apoptotic function. BID plays an important role in the apoptotic pathway downstream of death receptors such as TNF R1 and Fas. Cleavage by caspase 8 and myristoylation serve to activate BID, facilitating targeting to the mitochondria where it activates multidomain pro-apoptotic family members such as BAX or BAK, and activating the downstream apoptotMice in which Bid has been deleted undergo all normal developmental deaths. Aging Bid- deficient mice fail to maintain myeloid homeostasis, progressing to a fatal, clonal disorder that closely resembles human Chronic Myelomonocytic Leukemia (CMML). Thus, this single "BH3-only" protein thus plays a critical role in maintenance of normal myeloid homeostasis and tumor suppression. In addition to its role in apoptosis, we have uncovered a role for BID in regulating the DNA damage-induced intra-S phase checkpoint that does not require its death-promoting BH3 domain. Following DNA damage, BID is found in the nucleus, phosphorylated by ATM, and plays a role in the intra-S phase checkpoint. Thus, BID has two distinct and separable functions, an apoptotic function mediated by caspase cleavage and its BHS-domain, and a cell cycle/DMA repair function mediated by phosphorylation by the DNA damage kinase ATM. One of the central problems in the DNA damage and apoptotic pathways is how cells determine their response to DNA damage. Some cells arrest the cell cycle, and others undergo apoptosis. We hypothesize that BID acts at the interface between the DNA damage response and apoptosis, in position to execute the decision of a cell to undergo cell cycle arrest and initiate DNA repair or to undergo apoptosis. We propose to directly test this hypothesis by dissecting the mechanism of Bid function on both sides of this molecular switch. An understanding of the regulatory mechanisms that govern a cell's decision to activate cell cycle checkpoints or to undergo apoptosis has important implications for how cells respond to current cancer therapy, and should lead to important clues to new therapeutic targets.

描述（由申请人提供）：Bcl-2 家族构成细胞死亡途径中的关键检查点。 BID 是该家族“仅 BH3”子集的成员，需要其保守的 BH3 结构域来发挥其促凋亡功能。 BID 在 TNF R1 和 Fas 等死亡受体下游的细胞凋亡途径中发挥重要作用。 Caspase 8 的切割和肉豆蔻酰化可激活 BID，促进靶向线粒体，激活多结构域促凋亡家族成员（如 BAX 或 BAK），并激活下游细胞凋亡。Bid 被删除的小鼠会经历所有正常的发育死亡。衰老的 Bid 缺陷小鼠无法维持骨髓稳态，从而发展为一种致命的克隆性疾病，与人类慢性粒单核细胞白血病 (CMML) 非常相似。因此，这种单一的“仅 BH3”蛋白在维持正常骨髓稳态和抑制肿瘤方面发挥着关键作用。除了在细胞凋亡中的作用外，我们还发现了 BID 在调节 DNA 损伤诱导的 S 期内检查点方面的作用，该检查点不需要其促进死亡的 BH3 结构域。 DNA 损伤后，BID 出现在细胞核中，被 ATM 磷酸化，并在 S 期内检查点中发挥作用。因此，BID 具有两种不同且可分离的功能，一种是由 caspase 裂解及其 BHS 结构域介导的细胞凋亡功能，另一种是由 DNA 损伤激酶 ATM 磷酸化介导的细胞周期/DMA 修复功能。 DNA 损伤和细胞凋亡途径的核心问题之一是细胞如何确定其对 DNA 损伤的反应。一些细胞阻止细胞周期，而另一些则发生细胞凋亡。我们假设 BID 作用于 DNA 损伤反应和细胞凋亡之间的界面，能够执行细胞进行细胞周期停滞并启动 DNA 修复或进行细胞凋亡的决定。我们建议通过剖析该分子开关两侧的 Bid 功能机制来直接检验这一假设。了解控制细胞决定激活细胞周期检查点或进行细胞凋亡的调节机制对于细胞如何响应当前的癌症治疗具有重要意义，并且应该为新的治疗靶点提供重要线索。