This is a renewal application to further our investigation into the mechanism and significance of Bif-1-mediated Bax/Bak activation and mitochondrial morphogenesis in the context of tumorigenesis. Our studies have suggested that Bif-1 directly interacts with Bax in the mitochondrial outer membrane (MOM) and that both the physical and functional interactions between Bif-1 and Bax require the priming of monomer Bax by apoptotic stimuli that trigger Bax membrane recruitment, such as the BH3-only protein tBid. It appears that Bif-1 acts by promoting Bax homo-oligomerization rather than by facilitating Bax recruitment to the MOM. In addition, Bak activation is delayed as well in cells lacking Bif-1 during apoptosis. However, Bif-1 does not interact with Bak directly. Interestingly, our preliminary studies have demonstrated that Bif-1 selectively binds to the Bak inhibitor VDAC2. Bif-1, also known as endophilin B1, is a member of the endophilin protein family. Like other endophilins, Bif-1 is able to generate membrane curvature through its N-BAR domain, promoting Bax insertion into lipid bilayers. Moreover, Bif-1 has been shown to be required for fission of the MOM. Thus, we strongly suspect that Bif-1, in collaboration with BH3-only molecules, promotes Bax/Bak activation by altering the mitochondrial membrane shape. Moreover, Bif-1 and endophilin B2 (EndoB2) form stable heterodimers or tetramers in cells, suggesting that EndoB2 may also participate in the MOM remodeling associated with Bax/Bak activation during apoptosis. To further investigate the roles of endophilin B family proteins in Bax/Bak activation and mitochondrial morphogenesis, we propose the following Specific Aims: 1) To define the roles of Bif-1 and EndoB2 in the regulation of Bax/Bak activation, mitochondrial morphogenesis, and apoptosis;2) To determine whether Bif-1 interaction with VDAC2 plays a role in the regulation of Bak oligomerization, mitochondrial morphology, and apoptosis;3) To determine the roles of Bif-1 and EndoB2 in apoptosis, mitochondrial morphogenesis, and androgen-independent prostate cancer progression in mouse models under both physiological and pathological settings.

Public Health Relevance

Accumulating evidence suggests that Bif-1 is a tumor suppressor candidate. Successful implementation of this research will not only gain novel insight into the molecular mechanisms underlying the processes of Bax/Bak activation, mitochondrial morphogenesis and androgen-independent prostate cancer development, but will also contribute to the establishment of new strategies for the prevention and treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA082197-12A1
Application #
8121303
Study Section
Special Emphasis Panel (ZRG1-OBT-M (02))
Program Officer
Salnikow, Konstantin
Project Start
1999-08-01
Project End
2016-03-31
Budget Start
2011-06-01
Budget End
2012-03-31
Support Year
12
Fiscal Year
2011
Total Cost
$249,040
Indirect Cost
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Serfass, Jacob M; Takahashi, Yoshinori; Zhou, Zhixiang et al. (2017) Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection. J Biol Chem 292:10097-10111
Takahashi, Yoshinori; Tsotakos, Nikolaos; Liu, Ying et al. (2016) The Bif-1-Dynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rab11-positive reservoirs. Oncotarget 7:20855-68
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