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Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes. PLoS One 2012;7(2):e31569



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2-s2.0-84863165939 (requires institutional sign-in at Scopus site)   15 Citations


BACKGROUND: Tat-interactive protein 60 (Tip60) is a member of the MYST family of histone acetyltransferases. Studies using cultured cells have shown that Tip60 has various functions including DNA repair, apoptosis and cell-cycle regulation. We globally ablated the Tip60 gene (Htatip), observing that Tip60-null embryos die at the blastocyst stage (Hu et al. Dev.Dyn.238:2912;2009). Although adult heterozygous (Tip60(+/-)) mice reproduce normally without a haploinsufficient phenotype, stress caused by Myc over-expression induced B-cell lymphoma in Tip60(+/-) adults, suggesting that Tip60 is a tumor suppressor (Gorrini et al. Nature 448:1063;2007). These findings prompted assessment of whether Tip60, alternative splicing of which generates two predominant isoforms termed Tip60α and Tip60β, functions to suppress the cell-cycle in adult cardiomyocytes.

METHODOLOGY/PRINCIPAL FINDINGS: Western blotting revealed that Tip60α is the predominant Tip60 isoprotein in the embryonic heart, transitioning at neonatal stages to Tip60β, which is the only isoprotein in the adult heart wherein it is highly enriched. Over-expression of Tip60β, but not Tip60α, inhibited cell proliferation in NIH3T3 cells; and, Tip60-haploinsufficient cultured neonatal cardiomyocytes exhibited increased cell-cycle activity. To address whether Tip60β suppresses the cardiomyocyte cell-cycle in the adult heart, hypertrophic stress was induced in Tip60(+/+) and Tip(+/-) littermates via two methods, Myc over-expression and aortic banding. Based on immunostaining cell-cycle markers and western blotting cyclin D, stress increased cardiomyocyte cell-cycle mobilization in Tip60(+/-) hearts, in comparison with Tip60(+/+) littermates. Aortic-banded Tip60(+/-) hearts also exhibited significantly decreased apoptosis.

CONCLUSIONS/SIGNIFICANCE: These findings provide evidence that Tip60 may function in a tumor suppressor pathway(s) to maintain adult cardiomyocytes in replicative senescence.

Author List

Fisher JB, Kim MS, Blinka S, Ge ZD, Wan T, Duris C, Christian D, Twaroski K, North P, Auchampach J, Lough J


John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
John W. Lough PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Cycle
Cell Proliferation
Cellular Senescence
Histone Acetyltransferases
Lysine Acetyltransferase 5
Myocytes, Cardiac
NIH 3T3 Cells
Stress, Physiological
Tumor Suppressor Proteins