Education
B.S., Baldwin-Wallace College
PhD, Case Western Reserve University
PharmacologyPostdoctoral Training, La Jolla Institute for Allergy and Immunology
Postdoctoral Training, St. Jude Children’s Research Hospital
Awards
2012 - 2013
Young Scientist Cancer Research Fund
JJR Foundation2011 - 2012
P20 Pilot Grant
National Institutes of Health2011 - 2013
Basil O'Connor Award
March of Dimes2003 - 2006
Ruth Kirschstein NRSA
National Institutes of Health
Research
Postdoctoral Fellows: Kostas Floros Ph.D., Thibaud Renault Ph.D., Madhavika Serasinghe Ph.D.
Graduate Students: Rana Elkholi M.S., Derek Missert
Associate Researcher: James Asciolla
Visiting Scientist(s): Jessica Milian
A mitochondrion is a cell’s symbiotic friend and foe. The oxidative phosphorylation cascade is situated between the outer and inner mitochondrial membranes, which are a series of protein complexes responsible for ATP generation. Also between these membranes are pro-apoptotic factors that engage the core apoptotic machinery upon release into the cytoplasm. The integrity of the outer mitochondrial membrane (OMM) is key to preserving ATP generation and survival; it is also the ultimate target of pro-apoptotic signaling through the BCL-2 family when cellular damage accumulates or is beyond repair. The BCL-2 family consists of approximately twenty members, subdivided into anti-apoptotic (e.g., BCL-2, BCL-xL, MCL-1, and A1), pro-apoptotic effectors (e.g., BAK and BAX) and BH3-only proteins (e.g., BAD, BID, and PUMA). Through dynamic regulation of multiple proteins within each subfamily, the cellular milieu is integrated into either preserving or compromising the OMM.
The laboratory focuses on the mitochondrial pathway of apoptosis with particular interest in the BCL-2 family of proteins. The mitochondrial pathway of apoptosis is activated during metazoan development, and is utilized for maintenance of adult tissues following both physiological signaling and cellular stress scenarios. Importantly, the mitochondrial pathway of apoptosis is often engaged following chemotherapeutic treatment, yet malignant cells have devised clever mechanisms to block activation of this pathway to ensure survival. Our main goal is to understand the BCL-2 family in the context the cellular milieu with hopes to gain fundamental insights into the physiological and patho-physiological mechanisms of apoptosis.
The laboratory's primary research interests are to understand the relationships between BCL-2 proteins and mitochondrial physiology that are involved in cellular fate decisions. Despite an abundant literature, there are many unanswered questions regarding the primary functions and mechanisms of the BCL-2 proteins. Over the years, I established multiple approaches, unique model systems and numerous collaborations to gain compelling insights into BCL-2 family function.
Our current research interests are divided into three areas, but adopt a unified theme to decipher the interplay between the BCL-2 family, mitochondrial function and cell death pathways:
I. Define the function and regulation of BCL-2 family proteins.
II. What are the biochemical, physiological and structural consequences of protein·protein interactions within the BCL-2 family?
III. How do mitochondria influence BCL-2 family function and cell fate decisions?
Publications
Chipuk JE, McStay GP, Bharti A, Kuwana T, Clarke CJ, Siskind LJ, Obeid LM, Green DR. Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis. Cell 2012 March; 148(5): 988-1000.
Anvekar RA, Asciolla JJ, Missert DJ, Chipuk JE. Born to be alive: a role for the BCL-2 family in melanoma tumor cell survival, apoptosis, and treatment. Frontiers in Molecular Oncology 2011 Oct; 1(34).
Elkholi R, Floros KV, Chipuk JE. The Role of BH3-Only Proteins in Tumor Cell Development, Signaling, and Treatment. Genes & Cancer 2011 May; 2(5).
Garrison SP, Phillips DC, Jeffers JR, Chipuk JE, Parsons MJ, Rehg JE, Opferman JT, Green DR, Zambetti GP. Genetically defining the mechanism of PUMA- and BIM-induced apoptosis. Cell Death and Differentiation 2011 Oct;.
Du H, Wolf J, Schafer B, Moldoveanu T, Chipuk JE, Kuwana T. BH3 domains other than BIM and BID can directly activate BAX/BAK. The Journal of Biological Chemistry 2011 Jan; 286(1).
McAuley JL, Chipuk JE, Boyd KL, Van De Velde N, Green DR, McCullers JA. PB1-F2 proteins from H5N1 and 20th century pandemic influenza viruses cause immunopathology. PLoS Pathogens 2010; 6(7).
Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Molecular Cell 2010 Feb; 37(3).
Chipuk JE, Green DR. PUMA cooperates with direct activator proteins to promote mitochondrial outer membrane permeabilization and apoptosis. Cell Cycle 2009 Sep; 8(17).
Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? . Trends in Cell Biology 2008 April; 18(4): 157-164.
Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kurth MJ, Hinshaw J, Shaw J, Green DR, Nunnari J. Mitochondrial division inhibitors reveal the role of the mitochondrial division dynamin in BAX/BAK-dependent mitochondrial cytochrome c release. Developmental Cell 2008 February; 14(2): 193-204.
Green D, Chipuk J. Stabbed in the BAX. Nature 2008 October; 455(7216): 1047-1049.
Chipuk JE, Fisher JC, Dillon CP, Kuwana T, Kriwacki RW, Green DR. Mechanism of apoptosis induction by the inhibition of BCL-2 proteins. Proceedings of the National Academy of Science - USA 2008 Dec; 105(51): 20327-20332.
Chipuk JE, Green DR. Do inducers of apoptosis trigger caspase-independent cell death?. Nature Reviews Molecular Cellular Biology 2005 March; 6(3): 268-275.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR. BH3 domains of BH3-only proteins differentially regulate BAX-mediated membrane permeabilization both directly and indirectly. Molecular Cell 2005 Feb; 17(4): 525-35.
Chipuk JE, Bouchier-Hayes L, Newmeyer DD, Green DR. PUMA couples the nuclear and cytoplasmic pro-apoptotic function of p53. Science 2005 Sept; 309(5741): 1732-1735.
Spierings D, McStay GP, Saleh M, Bender C, Chipuk JE, Maurer U, Green DR. Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science 2005 Oct; 310(5745): 66-67.
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of BAX by p53 mediates mitochondrial outer membrane permeabilization and apoptosis. Science 2004 Feb; 303(5660): 1010-1014.
Chipuk JE, Maurer U, Green DR, Schuler M. Pharmacologic activation of p53 elicits BAX-dependent apoptosis in the absence of transcription. Cancer Cell 2003 Nov; 4(5): 371-381.
Industry Relationships
Physicians and scientists on the faculty of Mount Sinai School of Medicine often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Chipuk did not report having any of the following types of financial relationships with industry during 2011 and/or 2012: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://www.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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