Pro-apoptotic BID in DNA Damage and Leukemogenesis

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是该家族的“仅BH 3”子集的成员，并且需要其保守的BH 3结构域用于其促凋亡功能。BID在死亡受体如TNF R1和Fas的凋亡途径下游起重要作用。通过胱天蛋白酶8和豆蔻酰化的切割用于激活BID，促进靶向线粒体，在线粒体中其激活多结构域促凋亡家族成员如BAX或巴克，并激活下游凋亡基因。其中Bid已缺失的小鼠经历所有正常的发育死亡。衰老的Bid缺陷小鼠不能维持髓样稳态，发展成与人慢性粒单核细胞白血病（CMML）非常相似的致命性克隆性疾病.因此，这种单一的“仅BH 3”蛋白在维持正常骨髓稳态和肿瘤抑制中起关键作用。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期内检查点中的作用，该检查点不需要其促死BH 3结构域。DNA损伤后，BID在细胞核中被发现，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，由半胱天冬酶切割及其BHS结构域介导的凋亡功能，以及由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。一些细胞阻滞细胞周期，而另一些细胞经历凋亡。我们假设BID作用于DNA损伤反应和细胞凋亡之间的界面，在适当的位置执行细胞进行细胞周期停滞和启动DNA修复或进行细胞凋亡的决定。我们建议直接测试这一假设，通过解剖这一分子开关两侧的投标功能的机制。了解细胞决定激活细胞周期检查点或进行凋亡的调控机制对细胞如何对当前癌症治疗作出反应具有重要意义，并应导致新的治疗靶点的重要线索。

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.