Cordycepin (3′-deoxyadenosine) inhibits the growth of B16-BL6 mouse melanoma cells through the stimulation of adenosine A3 receptor followed by glycogen synthase kinase-3β activation and cyclin D1 suppression

Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3β seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3β. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.

Download Full-text

Stimulation of endothelin-1 gene expression by insulin via phosphoinositide-3 kinase–glycogen synthase kinase-3β signaling in endothelial cells

Life Sciences ◽

10.1016/j.lfs.2007.12.005 ◽

2008 ◽

Vol 82 (9-10) ◽

pp. 512-518 ◽

Cited By ~ 13

Author(s):

Zeran Yang ◽

Ji-Cheng Li

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Endothelin 1 ◽

Phosphoinositide 3 Kinase ◽

Stimulation Of

Download Full-text

Glycogen synthase kinase 3β and cyclin D1 expression in cervical carcinogenesis

Obstetrics & Gynecology Science ◽

10.5468/ogs.2016.59.6.470 ◽

2016 ◽

Vol 59 (6) ◽

pp. 470 ◽

Cited By ~ 3

Author(s):

Hyunsoo Park ◽

Myunghwa Lee ◽

Dae Woon Kim ◽

Seo Yoo Hong ◽

Hojung Lee

Keyword(s):

Cyclin D1 ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Cervical Carcinogenesis ◽

Glycogen Synthase Kinase 3Β

Download Full-text

Inhibition of glycogen synthase kinase-3β activity is sufficient to stimulate myogenic differentiation

AJP Cell Physiology ◽

10.1152/ajpcell.00068.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. C453-C462 ◽

Cited By ~ 63

Author(s):

Jos L. J. van der Velden ◽

Ramon C. J. Langen ◽

Marco C. J. M. Kelders ◽

Emiel F. M. Wouters ◽

Yvonne M. W. Janssen-Heininger ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Glycogen Synthase ◽

Muscle Growth ◽

Glycogen Synthase Kinase ◽

Skeletal Muscle Atrophy ◽

Glycogen Synthase Kinase 3Β ◽

Igf I ◽

Gsk 3Β ◽

Stimulation Of

Skeletal muscle atrophy is a prominent and disabling feature of chronic wasting diseases. Prevention or reversal of muscle atrophy by administration of skeletal muscle growth (hypertrophy)-stimulating agents such as insulin-like growth factor I (IGF-I) could be an important therapeutic strategy in these diseases. To elucidate the IGF-I signal transduction responsible for muscle formation (myogenesis) during muscle growth and regeneration, we applied IGF-I to differentiating C2C12 myoblasts and evaluated the effects on phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK-3β) signaling and myogenesis. IGF-I caused phosphorylation and inactivation of GSK-3β activity via signaling through the PI3K/Akt pathway. We assessed whether pharmacological inhibition of GSK-3β with lithium chloride (LiCl) was sufficient to stimulate myogenesis. Addition of IGF-I or LiCl stimulated myogenesis, evidenced by increased myotube formation, muscle creatine kinase (MCK) activity, and troponin I (TnI) promoter transactivation during differentiation. Moreover, mRNAs encoding MyoD, Myf-5, myogenin, TnI-slow, TnI-fast, MCK, and myoglobin were upregulated in myoblasts differentiated in the presence of IGF-I or LiCl. Importantly, blockade of GSK-3β inhibition abrogated IGF-I- but not LiCl-dependent stimulation of myogenic mRNA accumulation, suggesting that the promyogenic effects of IGF-I require GSK-3β inactivation and revealing an important negative regulatory role for GSK-3β in myogenesis. Therefore, this study identifies GSK-3β as a potential target for pharmacological stimulation of muscle growth.

Download Full-text

Laforin Negatively Regulates Cell Cycle Progression through Glycogen Synthase Kinase 3β-Dependent Mechanisms

Molecular and Cellular Biology ◽

10.1128/mcb.01334-08 ◽

2008 ◽

Vol 28 (23) ◽

pp. 7236-7244 ◽

Cited By ~ 12

Author(s):

Runhua Liu ◽

Lizhong Wang ◽

Chong Chen ◽

Yan Liu ◽

Penghui Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Cyclin D1 ◽

Tumor Suppression ◽

Cell Cycle Progression ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Cycle Progression ◽

Gsk 3Β

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.

Download Full-text

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.

Download Full-text