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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088347-05
Application #
8139701
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Thomas, John
Project Start
2007-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$383,609
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zinkel, S S; Yin, X M; Gross, A (2013) Rejuvenating Bi(d)ology. Oncogene 32:3213-3219
Biswas, S; Shi, Q; Wernick, A et al. (2013) The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice. Cell Death Differ 20:869-77
Liu, Y; Aiello, A; Zinkel, S S (2012) Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress. Cell Death Differ 19:1602-12
Yin, Huiyong; Vergeade, Aurelia; Shi, Qiong et al. (2012) Acetaminophen inhibits cytochrome c redox cycling induced lipid peroxidation. Biochem Biophys Res Commun 423:224-8
Liu, Yang; Vaithiyalingam, Sivaraja; Shi, Qiong et al. (2011) BID binds to replication protein A and stimulates ATR function following replicative stress. Mol Cell Biol 31:4298-309
Liu, Y; Bertram, C C; Shi, Q et al. (2011) Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ 18:841-52
Zinkel, Sandra S (2008) Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis. Methods Enzymol 442:231-50