Absence of AMPKα2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts

Jan 1, 2016The international journal of biochemistry & cell biology

Lack of AMPKα2 speeds up cell aging by increasing p16 in mouse embryonic fibroblast cells

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Abstract

Deletion of AMPKα2 in mouse embryonic fibroblasts led to accelerated cell senescence and increased levels of the cell cycle inhibitor p16.

AMPKα2 deletion resulted in spontaneous cell senescence, indicated by increased senescence-associated-β-galactosidase staining.
High-passaged fibroblasts from AMPKα2-deficient mice showed enhanced foci formation of a specific protein associated with chromatin changes.
The absence of AMPKα2 was linked to higher production of reactive oxygen species (ROS).
Knockdown of a specific protein, HBP1, reduced the levels of p16 and partially mitigated cellular senescence in AMPKα2-deleted cells.
Skin tissue from aged AMPKα2-deficient mice exhibited more pronounced fibroblast senescence compared to wild type mice.

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Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, delays aging process. However, the molecular mechanisms by which AMPKα isoform regulates cellular senescence remain largely unknown. The aim of this study was to determine if AMPKα deletion contributes to the accelerated cell senescence by inducing p16(INK4A) (p16) expression thereby arresting cell cycle. The markers of cellular senescence, cell cycle proteins, and reactive oxygen species (ROS) were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKα1, or AMPKα2 homozygous deficient (AMPKα1(-/-), AMPKα2(-/-)) mice by Western blot and cellular immunofluorescence staining, as well as immunohistochemistry (IHC) in skin tissue of young and aged mice. Deletion of AMPKα2, the minor isoform of AMPKα, but not AMPKα1 in high-passaged MEFs led to spontaneous cell senescence demonstrated by accumulation of senescence-associated-β-galactosidase (SA-β-gal) staining and foci formation of heterochromatin protein 1 homolog gamma (HP1γ). It was shown here that AMPKα2 deletion upregulates cyclin-dependent kinase (CDK) inhibitor, p16, which arrests cell cycle. Furthermore, AMPKα2 null cells exhibited elevated ROS production. Interestingly, knockdown of HMG box-containing protein 1 (HBP1) partially blocked the cellular senescence of AMPKα2-deleted MEFs via the reduction of p16. Finally, dermal cells senescence, including fibroblasts senescence evidenced by the staining of p16, HBP1, and Ki-67, in the skin of aged AMPKα2(-/-) mice was enhanced when compared with that in wild type mice. Taken together, our results suggest that AMPKα2 isoform plays a fundamental role in anti-oxidant stress and anti-senescence.

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Absence of AMPKα2 accelerates cellular senescence via p16 induction in mouse embryonic fibroblasts

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