Pro-apoptotic BID in DNA Damage and Leukemogenesis

描述(由申请人提供)：Bcl2家族构成了细胞死亡途径中的一个关键的检查点。BID是该家族“BH3-Only”子集的成员之一，需要其保守的BH3结构域才能发挥促凋亡功能。Bid在肿瘤坏死因子受体和Fas等死亡受体下游的凋亡途径中起重要作用。半胱氨酸天冬氨酸蛋白酶8的切割和肉豆蔻酰化作用有助于激活Bid，促进靶向线粒体，在那里它激活多结构域促凋亡家族成员，如Bax或BAK，并激活下游的apoptoMice，其中Bid被缺失，经历所有正常的发育死亡。衰老的BID缺陷小鼠无法维持髓系稳态，进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“BH3-Only”蛋白在维持正常的髓系稳态和抑制肿瘤方面起着关键作用。除了它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内的阶段检查点中发挥作用。因此，Bid具有两种截然不同的功能，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损伤和凋亡途径中的核心问题之一是细胞如何决定其对DNA损伤的反应。一些细胞阻止了细胞周期，另一些细胞发生了凋亡。我们假设Bid作用于DNA损伤反应和细胞凋亡之间的交界处，在执行细胞周期停滞和启动DNA修复或进行细胞凋亡的决定时起作用。我们建议通过解剖分子开关两侧的BID功能机制来直接检验这一假说。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控机制，对于细胞如何对当前的癌症治疗做出反应具有重要意义，并将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.