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

Kim, Min Jung; Kang, Jiyoung; Rho, Yoon-Hwa; Kim, Yun Sook; Kim, Dong–Sun; Bae, Young‐Seuk

doi:10.1016/j.gene.2008.10.020

Cited by 14 publications

(9 citation statements)

References 17 publications

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“…How does CK2 activity decrease with advancing age in C. elegans ? Because our previous studies demonstrated that DNA methylation and microRNAs (miRNAs) are primarily involved in CK2α gene silencing during replicative senescence of human cells [28–30], we speculate that the underlying cause of age-dependent CK2 downregulation in worms may be related to DNA methylation or miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

et al. 2017

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Studies show that a decrease in protein kinase CK2 (CK2) activity is associated with cellular senescence. However, the role of CK2 in organism aging is still poorly understood. Here, we investigated whether protein kinase CK2 (CK2) modulated longevity in Caenorhabditis elegans. CK2 activity decreased with advancing age in the worms. Knockdown of kin-10 (the ortholog of CK2β) led to a short lifespan phenotype and induced age-related biomarkers, including retardation of locomotion, decreased pharyngeal pumping rate, increased lipofuscin accumulation, and reduced resistance to heat and oxidative stress. The long lifespan of age-1 and akt-1 mutants was significantly suppressed by kin-10 RNAi, suggesting that CK2 acts downstream of AGE-1 and AKT-1. Kin-10 knockdown did not further shorten the short lifespan of daf-16 mutant worms but either decreased or increased the transcriptional activity of DAF-16 depending on the promoters of the target genes, indicating that CK2 is an upstream regulator of DAF-16 in C. elegans. Kin-10 knockdown increased production of reactive oxygen species (ROS) in the worms. Finally, the ROS scavenger N-acetyl-L-cysteine significantly counteracts the lifespan shortening and lipofuscin accumulation induced by kin-10 knockdown. Therefore, the present results suggest that age-dependent CK2 downregulation reduces longevity by associating with both ROS generation and the AGE-1-AKT-1-DAF-16 pathway in C. elegans.

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Section: Discussionmentioning

confidence: 99%

Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

et al. 2017

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“…Interestingly, the promoters for the regulatory subunit genes contain a similar combination of regulatory sites, and work by Pyerin and Ackerman (33) indicate that transcription of the catalytic and regulatory subunits occurs in a coordinate fashion. It was recently reported that downregulation of CK2 α and α′ during cellular senescence is mediated by promoter hypermethylation (42). In addition, DNA methylation also resulted in downregulation of Sp1, Ets and NFκB levels.…”

Section: Discussionmentioning

confidence: 99%

Thiazolidinediones Prevent PDGF-BB-induced CREB Depletion in Pulmonary Artery Smooth Muscle Cells by Preventing Upregulation of Casein Kinase 2 α′ Catalytic Subunit

Garat

Crossno²,

Sullivan³

et al. 2010

Journal of Cardiovascular Pharmacology

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The transcription factor CREB is diminished in smooth muscle cells (SMCs) in remodeled, hypertensive pulmonary arteries (PAs) in animals exposed to chronic hypoxia. Forced depletion of CREB in PA SMCs stimulates their proliferation and migration in vitro. PDGF produced in the hypoxic PA wall promotes CREB proteasomal degradation in SMCs via PI3Kinase/Akt signaling, which promotes phosphorylation of CREB at two casein kinase 2 (CK2) sites. Here we tested whether thiazolidinediones, agents that inhibit hypoxia-induced PA remodeling, attenuate SMC CREB loss. We found that the thiazolidinedione rosiglitazone prevented PA remodeling and SMC CREB loss in rats exposed to chronic hypoxia. Likewise, the thiazolidinedione troglitazone blocked PA SMC proliferation and CREB depletion induced by PDGF in vitro. Thiazolidinediones did not repress Akt activation by hypoxia in vivo or by PDGF in vitro. However, PDGF induced CK2 α′ catalytic subunit expression and activity in PA SMCs, and depletion of CK2 α′ subunit prevented PDGF-stimulated CREB loss. Troglitazone inhibited PDGF-induced CK2 α′ subunit expression in vitro and rosiglitazone blocked induction of CK2 catalytic subunit expression by hypoxia in PA SMCs in vivo. We conclude that thiazolidine-diones prevent PA remodeling in part by suppressing upregulation of CK2 and loss of CREB in PA SMCs.

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“…Analysis of the genes showing the greatest degree of hypermethylation in TRAMP; Dnmt1 ϩ/ϩ mice relative to TRAMP; Dnmt1 N/R mice at 24 weeks revealed that most of the hypermethylated regions are in promoter CpG islands (Table 3). With the exception of a small subset of these genes, including Csnk1g2, Ints6, and En1, most of the identified genes are not previously known to be regulated by DNA methylation (25,43,45).…”

Section: Methodsmentioning

confidence: 99%

Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

Kinney

Moser

Pascual

et al. 2010

Molecular and Cellular Biology

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Previous studies have shown that tumor progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model is characterized by global DNA hypomethylation initiated during early-stage disease and locus-specific DNA hypermethylation occurring predominantly in late-stage disease. Here, we utilized Dnmt1 hypomorphic alleles to examine the role of Dnmt1 in normal prostate development and in prostate cancer in TRAMP. Prostate tissue morphology and differentiation status was normal in Dnmt1 hypomorphic mice, despite global DNA hypomethylation. TRAMP; Dnmt1 hypomorphic mice also displayed global DNA hypomethylation, but were characterized by altered tumor phenotype. Specifically, TRAMP; Dnmt1 hypomorphic mice exhibited slightly increased tumor incidence and significantly increased pathological progression at early ages and, conversely, displayed slightly decreased tumor incidence and significantly decreased pathological progression at advanced ages. Remarkably, hypomorphic Dnmt1 expression abrogated local and distant site macrometastases. Thus, Dnmt1 has tumor suppressor activity in early-stage prostate cancer, and oncogenic activity in late stage prostate cancer and metastasis. Consistent with the biological phenotype, epigenomic studies revealed that TRAMP; Dnmt1 hypomorphic mice show dramatically reduced CpG island and promoter DNA hypermethylation in late-stage primary tumors compared to control mice. Taken together, the data reveal a crucial role for Dnmt1 in prostate cancer and suggest that Dnmt1-targeted interventions may have utility specifically for advanced and/or metastatic prostate cancer.Changes in DNA methyltransferase (Dnmt) expression and DNA methylation are observed in human prostate cancer (3, 38, 41). Of particular interest, genes with tumor suppressive function become hypermethylated and silenced, which correlates with the development of specific disease phenotypes (2,3,38). Although an association between prostate cancer and alterations in DNA methylation has been established, in vivo models are required to determine whether these changes functionally contribute to the disease. In this context, studies in which pharmacological inhibitors of Dnmts were shown to inhibit prostate cancer in murine models have proven informative (34, 56). However, it remains unknown whether genetic disruption of epigenetic components, such as Dnmts, also impacts prostate cancer development. This is a critical question since the pharmacological inhibitors of Dnmts have pleiotropic effects, including those unrelated to activation of methylationsilenced genes (21, 23, 31). Moreover, no studies to date have examined whether Dnmts or DNA methylation play roles in normal prostate development; this information is vital to fully understanding the effects that inhibiting DNA methylation may have on prostate cancer.Dnmt1 is a maintenance DNA methyltransferase that propagates preexisting DNA methylation patterns in genomic DNA (44). Dnmt1 also is involved in de novo DNA methylation in cancer cells and interacts with other ...

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

Cited by 14 publications

References 17 publications

Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

Thiazolidinediones Prevent PDGF-BB-induced CREB Depletion in Pulmonary Artery Smooth Muscle Cells by Preventing Upregulation of Casein Kinase 2 α′ Catalytic Subunit

Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

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