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: 7483035
• 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/7483035
• 关键词: Age; Aging; Apoptosis; Apoptotic; Area; Ataxia-Telangiectasia-Mutated protein kinase; BAK1 gene; BAX gene; BH3 Domain; Bax protein; Bone Marrow; Bone Marrow Transplantation; Caspase; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Death; Cell Nucleus; Cells; Cessation of life; Chronic Myelomonocytic Leukemia; DNA Damage; DNA Repair; Development; Disease; Equilibrium; Family; Family member; Homeostasis; Human; Lead; Maintenance; Mediating; Mitochondria; Molecular; Mus; Myelogenous; Myeloid Progenitor Cells; N-Myristoylation; Pathway interactions; Phase; Phosphorylation; Play; Positioning Attribute; Post-Translational Protein Processing; Proteins; Research; Research Personnel; Resistance; Role; Side; Signal Transduction; Surface; TNF gene; Testing; Tumor Necrosis Factor-alpha; Tumor Suppression; cancer therapy; caspase-8; cell injury; chronic leukemia; defined contribution; domain mapping; human TNF protein; leukemia; leukemogenesis; member; mutant; myristoylation; novel therapeutics; programs; receptor; repaired; response; therapeutic target; transcription factor

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家族在细胞死亡途径中构成了关键检查点。出价是该家族“仅BH3-”子集的成员，并要求其保守的BH3域才能促凋亡。投标在死亡受体（例如TNF R1和FAS）下游的凋亡途径中起重要作用。 caspase 8和肉豆蔻酰化的裂解可激活投标，促进靶向线粒体，在那里它激活多域的促凋亡家族成员，例如bax或bak，并激活下游的poptotmice，其中销售了所有正常发育的竞标。衰老的竞标不足小鼠无法维持髓样稳态，发展为致命的，克隆疾病，与人类慢性脊髓细胞性白血病（CMML）非常相似。因此，这种单一的“仅BH3”蛋白在维持正常髓样稳态和抑制肿瘤方面起着关键作用。除了其在凋亡中的作用外，我们还发现了竞标在调节DNA损伤引起的S相检查点中的作用，该检查点不需要其促进死亡的BH3结构域。在DNA损伤后，在核中发现了出价，被ATM磷酸化，并在S Intra Intra相相检查点中起作用。因此，投标具有两个不同的可分离函数，这是由胱天蛋白酶裂解及其BHS域介导的凋亡功能，以及通过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主要问题之一是细胞如何确定其对DNA损伤的反应。一些细胞阻止了细胞周期，而另一些细胞会经历凋亡。我们假设投标作用于DNA损伤反应和凋亡之间的界面，以便执行细胞对经过细胞周期停滞并启动DNA修复或进行凋亡的决定。我们建议通过剖析该分子开关两侧的投标机理直接检验该假设。对控制细胞激活细胞周期检查点或进行凋亡的决定的调节机制的理解对细胞如何应对当前的癌症治疗具有重要意义，并应为新的治疗靶标提供重要的线索。