Downregulation of protein kinase CKII is associated with cellular senescence

Abstract

Protein kinase CKII (CKII) plays a critical role in cell growth and proliferation. In this study, we examine how CKII activity is regulated during cellular senescence. Our results demonstrate that CKII activity apparently decreases during both replicative and H 2 O 2 -induced senescence in human diploid fibroblast IMR-90 cells. The mRNA and protein levels of CKIIa decreases significantly during replicative and H 2 O 2 -induced senescence, while only slight reduction in those of CKIIb is observed during replicative senescence. Treatment of IMR-90 cells with CKII inhibitors 5,6-dichloro-1-b-D D-ribofuranosylbenzimidazole and apigenin led cells to acquire a senescent phenotype as judged by the senescence-associated b-galactosidase marker and overexpression of p53 and p21 Waf-1 . Knockdown of CKIIa in IMR-90 cells by RNA interference also dramatically induced the senescent phenotype. In parallel, CKII activity was transcriptional downregulated in rat liver and testis with advancing age. Taken together, these results suggest that downregulation of CKII activity is tightly associated not only with cellular senescence but also with organism aging.

Oxidative Stress and Cell Senescence Combine to Cause Maximal Renal Tubular Epithelial Cell Dysfunction and Loss in an in vitro Model of Kidney Disease

“…One of the unusual outcomes was that the flavonoid API, used successfully here and elsewhere [19] to induce renal cell senescence, also caused increased lipid peroxidation (increased MDA), decreased TAC and the greatest mitochondrial dysfunction with or without concurrent H 2 O 2 . Lagoa et al [24] recently reported, using mitochondria isolated from rat brain and heart, that API (10 μ M ) inhibited the activity of Complex I of the electron transport chain by affecting the binding of the coenzyme substrate.…”

“…After dose-response studies (unpublished data), they were grown to 80-90% confluence and then treated for 18-24 h with 0.4 m M H 2 O 2 for oxidative stress, and 100 µ M apigenin (API) to induce renal cell senescence [19]. DMSO as a vehicle control was <1% in growth medium).…”

Silencing of the CKIIα and CKIIα' genes during cellular senescence is mediated by DNA methylation

“…Indeed, overexpression of CKIIα in the T cells of transgenic mice results in a high predisposition for lymphoma formation (Seldin and Leder, 1995). Our own previous data indicated an association between the decrease in CKII activity by down-regulation of CKIIα transcription and progressing cellular senescence (Ryu et al, 2006). In the present study, we demonstrate for the first time that CKIIα' is also down-regulated transcriptionally in senescent cells.…”

“…We have previously demonstrated that the levels of CKIIα protein and mRNA decrease in IMR-90 cells during senescence (Ryu et al, 2006). Epigenetic modifications, such as DNA methylation, have emerged as important mechanisms to silence genes (Bird, 2002).…”

“…We found that CKII inhibition in IMR-90 cells by CKII inhibitors or CKIIα siRNA can induce premature senescence of the cells (Ryu et al, 2006). In the present study, we show that knockdown of CKIIα' in IMR-90 cells by RNA interference also induces the senescent phenotype.…”