- ASSISTANT PROFESSOR Oncological Sciences
- ASSISTANT PROFESSOR Dermatology
B.S., Baldwin-Wallace College
Ph.D., Case Western Reserve University
Postdoctoral Training, La Jolla Institute for Allergy and Immunology
Postdoctoral Training, St. Jude Children’s Research Hospital
Dr. Harold and Golden Lamport Research Award
2013 - 2016
Basil O'Connor Phase-In Award
March of Dimes
2012 - 2014
Young Scientist Cancer Research Fund
2011 - 2013
Basil O'Connor Award
March of Dimes
2011 - 2013
P20 Pilot Grant
National Institutes of Health
2003 - 2006
Ruth Kirschstein NRSA
National Institutes of Health
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. We utilize several model systems to explore BCL-2 family function, including ethanol-induced stress and cellular models of melanoma.
Thibaud T. Renault Ph.D.
Madhavika N. Serasinghe Ph.D.
Rana Elkholi M.S.
Julie Sung B.S.
Shira Y. Wieder B.S.
Our current research interests are divided into three areas, but adopt a unified theme to decipher the interplay between mitochondrial function and cell death pathways:
I. What are the biochemical, physiological, and structural consequences of protein·protein interactions within the BCL-2 family?
II. How does the mitochondrial environment influence BCL-2 family function and the core cell death machinery?
III. How do oncogenic and tumor suppressor signals intersect with the core cell death machinery and metabolic pathways to regulate tumorigenesis and chemosensitivity?
Elkholi R, Renault TT, Serasinghe MN, Chipuk JE. Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy. Cancer & Metabolism 2014;.
Renault TT, Elkholi R, Bharti A, Chipuk JE. BH3 mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins. Journal of Biological Chemistry 2014 Oct;.
Chong RA, Wu K, Spratt DE, Yang Y, Lee C, Nayak J, Xu M, Elkholi R, Tappin I, Li J, Hurwitz J, Brown BD, Chipuk JE, Chen ZJ, Sanchez R, Shaw GS, Huang L, Pan ZQ. Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination. Proc Natl Acad Sci USA 2014 June 10; 111(23): 8434-9.
Serasinghe MN, Missert DJ, Asciolla JJ, Podgrabinska S, Wieder SY, Izadmehr S, Belbin G, Skobe M, Chipuk JE. Anti-apoptotic BCL-2 proteins govern cellular outcome following BRAFV600E inhibition and can be targeted to reduce resistance. Oncogene 2014 Mar 10;.
Zhang X, Lv H, Zhou Q, Elkholi R, Chipuk JE, Reddy MV, Reddy EP, Gallo JM. Preclinical pharmacological evaluation of a novel multiple kinase inhibitor, ON123300, in brain tumor models. Molecular Cancer Therapeutics 2014 May; 13(5): 1105-16.
Lopez-Rivera E, Jayaraman P, Parikh F, Davies MA, Ekmekcioglu S, Izadmehr S, Milton DR, Chipuk JE, Grimm EA, Estrada Y, Aguirre-Ghiso JA, Sikora AG. Inducible nitric oxide synthase drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2. Cancer Research 2014 Feb 15; 74(4): 1067-1078.
Elkholi R, Chipuk JE. How do I kill thee? Let me count the ways: p53 regulates PARP-1 dependent necrosis. BioEssays 2014 Jan; 36(1): 46-51.
Renault TT, Chipuk JE. Death upon a kiss: mitochondrial outer membrane composition and organelle communication govern sensitivity to BAK/BAX-dependent apoptosis. Chemistry & Biology 2014 Jan 16; 21(1): 114-123.
Fink MY, Chipuk JE. Survival of HER2-positive breast cancer cells: receptor signaling to apoptotic control centers. Genes & Cancer 2013 May 8; 4(5-6): 187-195.
Renault TT, Floros KV, Chipuk JE. BAK/BAX activation and cytochrome c release assays using isolated mitochondria. Methods 2013 June; 61(2): 146-155.
Beverly LJ, Howell LA, Hernandez-Corbacho M, Casson L, Chipuk JE, Siskind LJ. BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins. The Biochemical Journal 2013 May 15; 452(1): 111-9.
Renault TT, Chipuk JE. Getting away with murder: how do the BCL-2 family of proteins kill with immunity?. Annals of the New York Academy of Science 2013 May; 1285(1): 59-79.
Follis AV, Chipuk JE, Fisher JC, Yun MK, Grace CR, Nourse A, Baran K, Ou L, Min L, White SW, Green DR, Kriwacki RW. PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. Nature Chemical Biology 2013 Mar; 9(3): 163-8.
Renault TT, Chipuk JE. Inter-organellar communication with mitochondria regulates both the intrinsic and extrinsic pathways of apoptosis. Communicative & Integrative Biology 2013 March/April; 6(2): 1-4.
Anvekar RA, Asciolla JJ, Lopez-Rivera E, Floros KV, Izadmehr S, Elkholi R, Belbin G, Sikora AG, Chipuk JE. Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens. Cell Death and Disease 2012 Nov 15; 3(e420): 1-11.
Asciolla JJ, Renault TT, Chipuk JE. Examining BCL-2 family function with large unilamellar vesicles. Journal of Visualized Experiments 2012 Oct 5; 68: 1-6.
Greter M, Helft J, Chow A, Hashimoto D, Mortha A, Agudo-Cantero J, Bogunovic M, Gautier EL, Miller J, Leboeuf M, Lu G, Aloman C, Brown BD, Pollard JW, Xiong H, Randolph GJ, Chipuk JE, Frenette PS, Merad M. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 2012 Jun; 36(6): 1031-46.
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.
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 2012 Apr; 18(4): 642-9.
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): 523-37.
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).
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): 491-501.
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): 299-310.
Chipuk JE, Green DR. PUMA cooperates with direct activator proteins to promote mitochondrial outer membrane permeabilization and apoptosis. Cell Cycle 2009 Sep; 8(17): 2692-6.
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.
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai 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 2013 and/or 2014: 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://icahn.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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