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Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes.

ABSTRACT: 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 Tip60? and Tip60?, functions to suppress the cell-cycle in adult cardiomyocytes.Western blotting revealed that Tip60? is the predominant Tip60 isoprotein in the embryonic heart, transitioning at neonatal stages to Tip60?, which is the only isoprotein in the adult heart wherein it is highly enriched. Over-expression of Tip60?, but not Tip60?, inhibited cell proliferation in NIH3T3 cells; and, Tip60-haploinsufficient cultured neonatal cardiomyocytes exhibited increased cell-cycle activity. To address whether Tip60? 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.These findings provide evidence that Tip60 may function in a tumor suppressor pathway(s) to maintain adult cardiomyocytes in replicative senescence.

SUBMITTER: Fisher JB

PROVIDER: S-EPMC3279378 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes.

Fisher Joseph B JB Kim Min-Su MS Blinka Steven S Ge Zhi-Dong ZD Wan Tina T Duris Christine C Christian Desirae D Twaroski Kirk K North Paula P Auchampach John J Lough John J

PloS one 20120214 2

<h4>Background</h4>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 ...[more]

PMID: 22348108

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Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes.

Publications

Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes.

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