THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 297; no. 2; pp. H643 - H653
• Main Authors: Balakrishnan, Meenakshi P, Cilenti, Lucia, Mashak, Zineb, Popat, Paiyal, Alnemri, Emad S, Zervos, Antonis S
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2009
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Cell cycle; Cell Cycle - physiology; Cell Nucleus - enzymology; Cisplatin - pharmacology; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Coronary Artery Disease - physiopathology; Coronary vessels; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Enzymologic - physiology; Heart; HeLa Cells; High-Temperature Requirement A Serine Peptidase 2; Homeostasis - physiology; Humans; Hydrogen Peroxide - pharmacology; Kidney - cytology; Mitochondria, Heart - enzymology; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - metabolism; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium - enzymology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidants - pharmacology; Proteases; Proteins; Pyrimidinones - pharmacology; RNA, Messenger - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Substrate Specificity - physiology; Thiones - pharmacology; Transfection; Two-Hybrid System Techniques; Yeasts
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00234.2009

1 Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida; and 2 Center of Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania Submitted 9 March 2009 ; accepted in final form 2 June 2009 Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes. Omi/HtrA2; Thanatos-associated protein 5; coronary artery disease; apoptosis Address for reprint requests and other correspondence: A. S. Zervos, Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, Univ. of Central Florida, 12722 Research Parkway, Orlando, FL 32826 (e-mail: azervos{at}mail.ucf.edu )