title: Stress-induced cell-cycle activation in Tip60 haploinsufficient adult cardiomyocytes.
abstract: 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.
  
  
  RESULTS
  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
  These findings provide evidence that Tip60 may function in a tumor suppressor pathway(s) to maintain adult cardiomyocytes in replicative senescence.
authors.affiliation: Department of Cell Biology Neurobiology and Anatomy and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Fisher
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Kim
authors.forename: Steven
authors.initials: S
authors.lastname: Blinka
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
authors.forename: Tina
authors.initials: T
authors.lastname: Wan
authors.forename: Christine
authors.initials: C
authors.lastname: Duris
authors.forename: Desirae
authors.initials: D
authors.lastname: Christian
authors.forename: Kirk
authors.initials: K
authors.lastname: Twaroski
authors.forename: Paula
authors.initials: P
authors.lastname: North
authors.forename: John
authors.initials: J
authors.lastname: Auchampach
authors.forename: John
authors.initials: J
authors.lastname: Lough
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D057895:Haploinsufficiency; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000502:physiology; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D041681:NIH 3T3 Cells; D013312:Stress, Physiological / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5