Advanced glycation end-product-inhibited cell proliferation and protein expression of β-catenin and cyclin D1 are dependent on glycogen synthase kinase 3β in LLC-PK1 cells

ABSTRACT Glycogen synthase kinase 3β (GSK-3β) represses cell cycle progression by directly phosphorylating cyclin D1 and indirectly regulating cyclin D1 transcription by inhibiting Wnt signaling. Recently, we reported that the Epm2a-encoded laforin is a GSK-3β phosphatase and a tumor suppressor. The cellular mechanism for its tumor suppression remains unknown. Using ex vivo thymocytes and primary embryonic fibroblasts from Epm2a −/− mice, we show here a general function of laforin in the cell cycle regulation and repression of cyclin D1 expression. Moreover, targeted mutation of Epm2a increased the phosphorylation of Ser9 on GSK-3β while having no effect on the phosphorylation of Ser21 on GSK-3α. In the GSK-3β+/+ but not the GSK-3β−/− cells, Epm2a small interfering RNA significantly enhanced cell growth. Consistent with an increased level of cyclin D1, the phosphorylation of retinoblastoma protein (Rb) and the levels of Rb-E2F-regulated genes cyclin A, cyclin E, MCM3, and PCNA are also elevated. Inhibitors of GSK-3β selectively increased the cell growth of Epm2a +/+ but not of Epm2a −/− cells. Taken together, our data demonstrate that laforin is a selective phosphatase for GSK-3β and regulates cell cycle progression by GSK-3β-dependent mechanisms. These data provide a cellular basis for the tumor suppression activity of laforin.

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Keratin 19 interacts with GSK3β to regulate its nuclear accumulation and degradation of cyclin D3

Molecular Biology of the Cell ◽

10.1091/mbc.e21-05-0255 ◽

2021 ◽

Vol 32 (21) ◽

Author(s):

Pooja Sharma ◽

Sarah Tiufekchiev ◽

Victoria Lising ◽

Seung Woo Chung ◽

Jung Soo Suk ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Glycogen Synthase ◽

Cyclin D3 ◽

Glycogen Synthase Kinase ◽

Nuclear Accumulation ◽

Glycogen Synthase Kinase 3Β ◽

Keratin 19

Keratin 19 (K19) inhibits glycogen synthase kinase-3β (GSK3β) accumulation in the nucleus, preventing cyclin D3 degradation. K19 physically interacts with GSK3β, and this interaction requires Ser 10 and 35 of K19. Mutating either residues decreased cyclin D3 levels and cell proliferation. The K19–GSK3β–cyclin D3 pathway also regulates the sensitivity of cancer cells to CDK4/6 inhibitors.

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Noxious Stimulation Attenuates Ketamine-induced Neuroapoptosis in the Developing Rat Brain

Anesthesiology ◽

10.1097/aln.0b013e31825ae693 ◽

2012 ◽

Vol 117 (1) ◽

pp. 64-71 ◽

Cited By ~ 56

Author(s):

Jia-Ren Liu ◽

Qian Liu ◽

Jing Li ◽

Chongwha Baek ◽

Xiao Hui Han ◽

...

Keyword(s):

Protein Kinase ◽

Cyclin D1 ◽

Caspase 3 ◽

Glycogen Synthase ◽

Protein Kinase B ◽

Glycogen Synthase Kinase ◽

Terminal Deoxynucleotidyl Transferase ◽

Noxious Stimulation ◽

Glycogen Synthase Kinase 3Β ◽

Rat Pups

Background Ketamine induces neuroapoptosis in neonatal rodents. However, these experimental paradigms were performed without concurrent noxious stimulation, a condition that does not reflect the interaction of anesthesia and surgical stimulation. Noxious stimulation with and without concurrent analgesic drugs has been shown to have divergent patterns of neuronal activation and cell death. We hypothesized that concurrent noxious stimulation would attenuate ketamine-induced caspase-3 activation. Methods Postnatal day 7 Sprague-Dawley rat pups were randomized to a 6-h exposure to ketamine with and without peripheral noxious stimulation by intraplantar injection of complete Freund's adjuvant. A cohort of naïve rat pups with and without complete Freund's adjuvant injections served as control subjects. Neuroapoptosis was measured by cleaved caspase-3 expression and terminal deoxynucleotidyl-transferase mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining. In order to determine if concurrent noxious simulation altered the expression of cell survival and cell cycle proteins, levels of protein kinase B and glycogen synthase kinase-3β and cyclin D1 were measured. Results Ketamine induced a significant increase in cleaved caspase-3 expression and terminal deoxynucleotidyl-transferase mediated 2'-deoxyuridine 5'-triphosphate nick end labeling staining with increases in cyclin D1 levels. Concurrent noxious stimulation with ketamine attenuated caspase-3 activation and maintained cyclin D1 levels. Phosphorylation of protein kinase B and glycogen synthase kinase-3β was not definitively altered under these conditions. Conclusion The administration of ketamine with concurrent noxious stimulation results in the attenuation of the neuroapoptotic response. These findings suggest that concurrent surgery and procedural pain attenuates ketamine-induced neuroapoptosis.

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