Title

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

Authors

Authors

M. P. Balakrishnan; L. Cilenti; Z. Mashak; P. Popat; E. S. Alnemri;A. S. Zervos

Comments

Authors: contact us about adding a copy of your work at STARS@ucf.edu

Abbreviated Journal Title

Am. J. Physiol.-Heart Circul. Physiol.

Keywords

Omi/HtrA2; Thanatos-associated protein 5; coronary artery disease; apoptosis; ANTI-APOPTOTIC PROTEIN; FLOW CYTOMETRIC ASSAY; DNA-BINDING DOMAIN; SERINE-PROTEASE; C-ELEGANS; ISCHEMIA/REPERFUSION INJURY; CASPASE; ACTIVITY; HTRA2; KINASE; ISCHEMIA; Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular; Disease

Abstract

Balakrishnan MP, Cilenti L, Mashak Z, Popat P, Alnemri ES, Zervos AS. THAP5 is a human cardiac-specific inhibitor of cell cycle that is cleaved by the proapoptotic Omi/HtrA2 protease during cell death. Am J Physiol Heart Circ Physiol 297: H643-H653, 2009. First published June 5, 2009; doi:10.1152/ajpheart.00234.2009.-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.

Journal Title

American Journal of Physiology-Heart and Circulatory Physiology

Volume

297

Issue/Number

2

Publication Date

1-1-2009

Document Type

Article

Language

English

First Page

H643

Last Page

H653

WOS Identifier

WOS:000268348200020

ISSN

0363-6135

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