Professor, Department of Medicine (Cardiology)
Professor, Department of Cell Biology
Director, Wilf Family Cardiovascular Research Institute
The Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease
Cell Death: Fundamental Mechanisms and Roles in Human Disease
The most basic decision that any cell makes is to grow, differentiate, or die. Our laboratory is interested in basic mechanisms of cell death, and the roles of cell death in normal biology and human disease.
From a fundamental perspective, we are particularly interested in how different cell death pathways interconnect. In previous and ongoing work, we have explored this question using ARC, an endogenous inhibitor of apoptosis with the unusual property of inhibiting both extrinsic (death receptor) and intrinsic (mitochondrial/ER) apoptosis pathways (see Nam et al. Molecular Cell, 2004; Foo et al. PNAS, 2007; and others below). Our basic interests are currently focused on understanding how the pathways that mediate apoptotic and non-apoptotic cell death interconnect in what may be a unified program of cell death. In particular, we would like to understand the factors that determine whether a cell dies by apoptosis versus necrosis in the mitochondrial death pathway (see Whelan et al. PNAS, 2012). These studies involve a wide array of approaches including molecular and cellular biology, biochemistry, and chemical, mouse, and lower organism genetics.
Although our disease-related interests have ranged from cancer (see Wu et al. JBC, 2010; Medina-Ramirez et al. Cancer Res, 2011) to diabetes (see McKimpson et al. Diabetes, 2012), our major contributions involve heart disease, including myocardial infarction ("heart attack") and heart failure (see reviews Whelan et al. Annu Rev Physiol, 2010; Kung et al. Circ Res, 2011; Konstantinidis et al. Arterioscler Thromb Vasc Biol, 2012). In collaboration with Dr. Evripidis Gavathiotis (Department of Biochemistry), we are employing a powerful combination of chemical biology, structural biology, biochemistry, molecular and cellular biology, and small and large animal in vivo models in an attempt to translate basic insights into cardiac cell death mechanisms into novel small molecule therapies to decrease heart damage during heart attacks. We are also employing a small molecule approach to limit the deaths of transplanted cardiac progenitor cells.
Wencker D, Chandra M, Nguyen KT, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest, 2003. 111: 1497-1504.
Nam YJ, Mani K, Ashton AW, Peng CF, Krishnamurthy B, Hayakawa Y, Lee P, Korsmeyer SJ, Kitsis RN. Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Mol Cell, 2004. 15: 901-912.
MercierI, Vuolo M, Madan R, Xue X, Levalley AJ, Ashton AW, Jasmin JF, Czaja MT, Lin EY, Armstrong RC, Pollard JW, Kitsis RN. ARC, an apoptosis suppressor limited to terminally differentiated cells, is induced in human breast cancer and confers chemo- and radiation-resistance. Cell Death Differ, 2005. 12: 682-686.
Pajvani UB, Trujillo ME, Combs TP, Iyengar P, Jelicks L, Roth KA, Kitsis RN, Scherer, PE. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med, 2005. 11: 797-803.
Kitsis RN, Jialal I. Inhibiting CRP to limit myocardial damage during acute myocardial infarction? New Engl J Med, 2006. 355: 513-515.
Nam YJ, Mani K, Wu L, Peng CF, Calvert JW, Foo RSY, Krishnamurthy B, Miao W, Ashton AW, Lefer DJ, Kitsis RN. The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant. J Biol Chem, 2007. 282: 5522-5528.
Foo RSY, Chan LK, Kitsis RN, Bennett MR. Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2. J Biol Chem, 2007. 282: 5529-5535.
Kitsis RN, Peng CF, Cuervo AM. Eat your heart out. Nat Med, 2007. 13: 539-541.
Foo RSY, Nam YJ, Ostreicher MJ, Metzl MD, Whelan RS, Peng CF, Ashton AW, Fu W, Mani K, Chin SF, Provenzano E, Ellis I, Figg N, Pinder S, Bennett MR, Caldas C, Kitsis RN. Regulation of p53 tetramerization and nuclear export by ARC. Proc Natl Acad Sci (USA), 2007. 104: 20826-20831.
Mercier I, Vuolo M, Jasmin J-F, Medina CM, Williams M, Mariadason JM, Qian H, Xue X, Pestell RG, Lisanti MP, Kitsis RN. ARC (Apoptosis Repressor with Caspase Recruitment Domain) is a novel marker of human colon cancer. Cell Cycle, 2008. 7: 1640-1647.
Park M, Shen YT, Gaussin V, Heyndrickx GR, Bartunek J, Resuello RG, Natividad FF, Kitsis RN, Vatner DE, Vatner SF.Apoptosis predominates in non-myocytes in heart failure. Am J Physiol Heart Circ Physiol, 2009. 297: H785-H791.
Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol, 2010. 72: 19-44.
Wu L, Nam YJ, Peng CF, Crow MT, Kitsis RN. Induction of the apoptosis inhibitor ARC by Ras in human cancers. J Biol Chem, 2010. 285: 19235-19245.
Kung G, Konstantinidis K, Kitsis RN. Programmed necrosis – not apoptosis – in the heart. Circ Res, 2011. 108: 1017-1036. Circulation Research reports that this article was downloaded 1,990 times in the first 30 days of publication.
Feng D, Tang Y, Kwon H, Zong H, Hawkins M, Kitsis RN, Pessin, JE. High-fat diet-induced adipocyte cell death occurs through a cyclophilin D intrinsic signaling pathway independent of adipose tissue inflammation. Diabetes, 2011. 60: 2134-2143.
Zaiman A, Damico R, Thoms-Chesley A, Files DC, Kesari P, Johnston L, Swaim M, Mozhammel S, Myers AC, Halushka M, El-Haddad H, Shimoda LA, Peng CF, Hassoun PM, Champion HC, Kitsis RN, Crow MT. A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension. Circulation, 2011. 124: 2533-2542.
Medina-Ramirez CM, Goswami S, Smirnova T, Bamira D, Benson B, Ferrick N, Segall J, Pollard JW, Kitsis RN. Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance. Cancer Res, 2011. 71: 7705-7715.
Whelan RS, Konstantinidis K, Wei AC, Chun Y, Reyna DE, Jha S, Yang Y, Calvert JW, Lindsten T, Thompson CB, Crow MT, Gavathiotis E, Dorn II GW 2nd, O’Rourke B, Kitsis RN. Bax regulates primary necrosis through mitochondrial dynamics. Proc Natl Acad Sci (USA), 2012. 109: 6566-6571.
Konstantinidis K, Kitsis RN. Escaped DNA inflames the heart. Nature, 2012. 485: 179-180.
Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscler Thromb Vasc Biol, 2012. 32: 1552-1562.
Gavrilov, S, Nuehrenberg TG, Ashton AW, Peng CF, Moore JC, Konstantinidis K, Mummery CL, Kitsis RN. Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells. Differentiation, 2012. 84: 176-184.
McKimpson WM, Weinberger J, Czerski L, Zheng M, Crow MT, Pessin JE, Chua SC Jr, Kitsis RN. The apoptosis inhibitor ARC alleviates the ER stress response to promote beta-cell survival. Diabetes, 2012 Aug 29. [Epub ahead of print].
Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.
Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room G46
Bronx, NY 10461