|Institution||College of Medicine|
|Address||500 University Drive Hershey PA 17033|
Lois High Berstler Professor, Pediatrics and Pharmacology
Director, Pediatric Molecular Oncology Program
SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):
Pharmacology, Penn State Hershey Children’s Hospital, Penn State Hershey Cancer Institute, The Huck Institutes of the Life Sciences
GRADUATE PROGRAM AFFILIATIONS:
Cell and Molecular Biology, Pharmacology, Biomedical Sciences: Translation Therapeutics Option, Integrative Biosciences: Molecular Medicine
B.S., University of Tsukuba, 1987
Ph.D., University of Tsukuba, 1992
Postdoctoral Training, Burnham Institute, 1993-1998
Research in this laboratory is concerned with understanding the interplay of autophagy (self-eating) and apoptosis (self-killing) in the context of tumorigenesis and drug resistance. In addition, targeting of these two closely related but distinct self-destructive processes for anticancer drug discovery and development is another major interest of our research group. We discovered a novel tumor suppressor, Bif-1, that activates not only apoptosis but also autophagy. Bif-1 is involved in the conformational activation of Bax, a key pro-apoptotic Bcl-2 family member, at the mitochondria during apoptosis. Bif-1 interacts with BECN1 through UVRAG and regulates autophagosome formation and Atg9 trafficking during nutrient starvation. The expression of Bif-1 is decreased in various human cancers, and the deletion of Bif-1 promotes tumor development in mouse models. Our work on AMPK association with ULK1 was among the first to link a cellular energy sensor to the core autophagy machinery. We found that AMPK directly binds to ULK1, and this interaction is required for ULK1-mediated autophagy. Our studies unveiled a dual-armed intracellular death-inducing signaling complex (iDISC) that assembles on the autophagosomal membrane to mediate caspase-8 activation and initiation of the apoptotic cascade. This work has significant translational impact in identifying a mechanism by which the survival process of autophagy can be switched towards cell death to enhance the therapeutic efficacy of anticancer drugs. In addition, our group has identified the natural product marinopyrrole A (maritoclax) and its derivatives as a novel class of Mcl-1 inhibitors that antagonize Mcl-1 and overcome multidrug resistance in hematological malignancies by targeting Mcl-1 for proteasomal degradation. This unique mechanism of action is in sharp contrast to canonical BH3 mimetics that exert their inhibitory function through disruption of pro- and anti-apoptotic Bcl-2 family protein complexes. The ultimate goal of our research is to translate basic science discoveries to the development of new approaches for the treatment and prevention of cancer.
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