Stress‐Induced Cell‐Cycle Mobilization in Tip60‐Heterozygous Hearts

In cultured cells, Tat‐interactive protein 60kD (Tip60), a member of the MYST family of HATs, regulates functions including DNA repair, apoptosis and cell‐cycle transit. We globally ablated the Tip60 gene ( Htatip ) in mice, revealing that null embryos die at the blastocyst stage ( Dev. Dyn. 238:2912;2009). Although heterozygous mice reproduce normally with no phenotype, stress induced by c‐Myc over‐expression pre‐disposes B‐cell lymphoma, indicating that Tip60 is a tumor suppressor ( Nature 448:1063;2007). This prompted us to assess whether Tip60 suppresses proliferation of adult cardiomyocytes, wherein it is highly enriched as Tip60β isoprotein, transitioning from Tip60α dominance at proliferative stages of heart development. To elicit a haploinsufficient phenotype in adult hearts, stress was induced in Tip60 +/+ and Tip +/− littermates by c‐Myc over‐expression and aortic banding. Immunochemical probing of cell‐cycle markers including phosphohistone‐H3, Ki‐67, BrdU and cyclin‐D revealed that c‐Myc mobilized the cardiomyocyte cell‐cycle in Tip60 +/− hearts, in significant excess of that observed in Tip60 +/+ littermates. Stress due to aortic banding yielded similar results, which also included significantly decreased apoptosis in hearts of Tip60 +/− heterozygotes. These findings indicate that Tip60 functions to maintain adult cardiomyocytes in replicative senescence. Supported by NIH HL089471