Pro-apoptotic BID in DNA Damage and Leukemogenesis

描述（由申请人提供）：Bcl-2家族在细胞死亡途径中构成一个关键的检查点。BID是该家族“仅限BH3”亚群的成员，其促凋亡功能需要保守的BH3结构域。BID在TNF R1、Fas等死亡受体下游的凋亡通路中发挥重要作用。caspase 8的切割和肉豆蔻酰化有助于激活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，并激活下游凋亡。BID缺失的小鼠经历所有正常的发育性死亡。衰老Bid缺陷小鼠不能维持髓细胞稳态，发展为一种致命的克隆性疾病，与人类慢性髓细胞白血病（CMML）非常相似。因此，这种单一的“BH3-only”蛋白在维持正常骨髓稳态和抑制肿瘤中起着关键作用。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（不需要其促进死亡的BH3结构域）中的作用。DNA损伤后，在细胞核中发现BID，被ATM磷酸化，并在s期检查点中发挥作用。因此，BID具有两种截然不同且可分离的功能，一种是由caspase切割及其bhs结构域介导的凋亡功能，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损伤和凋亡途径的核心问题之一是细胞如何决定它们对DNA损伤的反应。一些细胞停止细胞周期，另一些细胞凋亡。我们假设BID在DNA损伤反应和细胞凋亡之间的界面起作用，在执行细胞周期阻滞和启动DNA修复或细胞凋亡的决定的位置。我们建议通过剖析该分子开关两侧的Bid功能机制来直接验证这一假设。了解细胞决定激活细胞周期检查点或经历细胞凋亡的调节机制对细胞如何对当前的癌症治疗作出反应具有重要意义，并且应该为新的治疗靶点提供重要线索。

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.