Does Tip60 Regulate the Cardiomyocyte Cell‐cycle?

Abstract

Tat‐Interactive Protein 60 (Tip60), a putative tumor suppressor, is a member of the MYST family of histone acetyltransferases (HATs). Tip60 function may include DNA repair, transcriptional co‐activation/repression, apoptosis, and cell‐cycle regulation. Alternative splicing of Tip60 mRNA creates α (60kD) and β (53kD) isoproteins, both of which are expressed in embryonic hearts. However, Tip60α becomes extinguished in neonatal hearts as proliferation subsides, leaving Tip60β as the sole isoprotein in adult heart. The role of Tip60 is unknown in adult cardiomyocytes, wherein we hypothesize that Tip60β maintains the G0 cell‐cycle state while promoting apoptosis. We targeted the Tip60 gene, observing that although homozygous deletion causes embryonic lethality, heterozygous deletion has no adult phenotype in the absence of stress. Therefore, two approaches, both of which induce hypertrophy, were used to stress Tip60+/− adult hearts: (i) physical stress via aortic banding and (ii) genetic stress via c‐Myc over‐expression. Both stressors caused the predicted outcomes of increased myocardial cell‐cycle activity and reduced apoptosis. These results support the hypothesis that Tip60 inhibits the cell‐cycle in adult cardiomyocytes, a possibility to be investigated using conditionally‐targeted mice that should enable reduction of Tip60β in myocardium to haploinsufficient levels.Grant Funding Source: American Heart Association; Grant Number: 0810108Z