Enhanced glycogenesis is involved in cellular senescence via GSK3/GS modulation

Abstract

SummaryGlycogen biogenesis and its response to physiological stimuli have often been implicated in age-related diseases. However, their direct relationships to cell senescence and aging have not been clearly elucidated. Here, we report the central involvement of enhanced glycogenesis in cellular senescence. Glycogen accumulation, glycogen synthase (GS) activation, and glycogen synthase kinase 3 (GSK3) inactivation commonly occurred in diverse cellular senescence models, including the liver tissues of aging F344 rats. Subcytotoxic concentrations of GSK3 inhibitors (SB415286 and LiCl) were sufficient to induce cellular senescence with increased glycogenesis. Interestingly, the SB415286-induced glycogenesis was irreversible, as were increased levels of reactive oxygen species and gain of senescence phenotypes. Blocking GSK3 activity using siRNA or dominant negative mutant (GSK3β β β β -K85A) also effectively induced senescence phenotypes, and GS knock-down significantly attenuated the stress-induced senescence phenotypes. Taken together, these results clearly demonstrate that augmented glycogenesis is not only common, but is also directly linked to cellular senescence and aging, suggesting GSK3 and GS as novel modulators of senescence, and providing new insight into the metabolic backgrounds of aging and aging-related pathogenesis.

Deregulated GSK3 Sustains Gastrointestinal Cancer Cells Survival by Modulating Human Telomerase Reverse Transcriptase and Telomerase

“…The putative role of GSK3β for sustaining cancer cells survival may therefore be due in part to effects on hTERT expression and telomerase activity, as well as on cellular senescence. The latter effect may be consistent with a recent report that enhanced glycogenesis is directly linked to cellular senescence through modulation of GSK3α/β and glycogen synthase (45).…”

Sterol Regulatory Element-binding Protein (SREBP)-1-mediated Lipogenesis Is Involved in Cell Senescence

“…However, we also observed that knocking down SREBP-1 below the level of control cells by using high dose siRNA also induced growth arrest (data not shown), suggesting that the well balanced regulation of lipogenesis is required to maintain normal cellular function, and the fine control of SREBP-1 activation is essential to control senescence. In addition, our previous study proved that glycogen synthase kinase 3 (GSK3) is commonly inactivated by being phosphorylated and is also importantly involved in all the cell senescence systems (DFO-and H 2 O 2 -induced, and replicative senescence) employed in this study (27). GSK3 is known to modulate SREBP1 activity through phosphorylation-mediated ubiquitination (21).…”

“…Organelles of Senescent Cells-First, we examined changes in mass of all cellular organelles, especially membranous ones, in stressinduced senescence triggered by DFO and H 2 O 2 as described previously (7,26,27). Subcellular organelles were stained with organelle-specific fluorescent dyes, and their masses were estimated by flow cytometric analysis (Fig.…”

The Ubiquitin-like with PHD and Ring Finger Domains 1 (UHRF1)/DNA Methyltransferase 1 (DNMT1) Axis Is a Primary Regulator of Cell Senescence

“…Senescence-associated ␤-Galactosidase Activity Staining-SA-␤-gal activity was assayed at pH 6.0 as described previously (38). The stain was visible for 12 h after incubation at 37°C.…”