Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death

Cross, Darren A.E.; Culbert, Ainsley A.; Chalmers, Katy A; Facci, Laura; Skaper, Stephen D.; Reith, Alastair D.

doi:10.1046/j.1471-4159.2001.t01-1-00251.x

Cited by 345 publications

(193 citation statements)

References 45 publications

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“…4A). The levels of SERCA2 also increased 216% compared to control cells by 6 h following treatment with 5 μM SB216763, a specific GSK3 inhibitor [7] (Fig. 4B).…”

Section: Resultsmentioning

confidence: 87%

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

King¹,

Gandy²,

Bijur³

2006

Experimental Cell Research

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The ubiquitously expressed protein glycogen synthase kinase-3 (GSK3) is constitutively active, however its activity is markedly diminished following phosphorylation of Ser21 of GSK3α and Ser9 of GSK3β. Although several kinases are known to phosphorylate Ser21/9 of GSK3, for example Akt, relatively much less is known about the mechanisms that cause the dephosphorylation of GSK3 at Ser21/9. In the present study KCl-induced plasma membrane depolarization of SH-SY5Y cells, which increases intracellular calcium concentrations caused a transient decrease in the phosphorylation of Akt at Thr308 and Ser473, and GSK3 at Ser21/9. Overexpression of the selective protein phosphatase-1 inhibitor protein, inhibitor-2, increased basal GSK3 phosphorylation at Ser21/9 and significantly blocked the KCl-induced dephosphorylation of GSK3β, but not GSK3α. The phosphorylation of Akt was not affected by the overexpression of inhibitor-2. GSK3 activity is known to affect sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) levels. Overexpression of inhibitor-2 or treatment of cells with the GSK3 inhibitors lithium and SB216763 increased the levels of SERCA2. These results indicate that the protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation induced by KCl and that GSK3 activity regulates SERCA2 levels. KeywordsAkt; glycogen synthase kinase-3; inhibitor-2; protein phosphatase-1; sarcoplasmic/endoplasmic reticulum calcium ATPase

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“…4A). The levels of SERCA2 also increased 216% compared to control cells by 6 h following treatment with 5 μM SB216763, a specific GSK3 inhibitor [7] (Fig. 4B).…”

Section: Resultsmentioning

confidence: 87%

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

King¹,

Gandy²,

Bijur³

2006

Experimental Cell Research

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“…These data suggest that UCN-01 inhibited Akt, removing the inhibition on GSK3b, and likely other proapoptotic proteins including caspase-9. Although the downstream action of GSK3b is not clearly delineated, overexpression of GSK3b-induced apoptosis in primary neuronal cultures, and GSK3b inhibitors blocked the apoptotic response induced by its over expression (Cross et al 2001). In SH-SY5Y cells, dominant negative GSK3b, or inhibition of phosphatidylinositol-3-kinase activated GSK3b and induced neurite retraction (Sanchez et al 2001).…”

Section: Discussionmentioning

confidence: 99%

UCN‐01 alters phosphorylation of Akt and GSK3β and induces apoptosis in six independent human neuroblastoma cell lines

Shankar¹,

Krupski²,

Parashar³

et al. 2004

Journal of Neurochemistry

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In this study we evaluated UCN-01, a small molecule that inhibits protein kinases by interacting with the ATP-binding site, as a potential anti-cancer agent for neuroblastoma. UCN-01 was effective at inducing apoptosis in six neuroblastoma cell lines with diverse cellular and genetic phenotypes. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), terminal deoxynucleotidyl transferase-mediated dUTP nickend-labeling (TUNEL) assays, detection of active caspase-3 and cleaved poly ADP-ribose polymerase (PARP) confirmed that UCN-01 induced apoptosis. Cell cycle analysis determined that the UCN-01 treated cells accumulated in S phase by 16 h. Unlike vinblastine and docetaxel that increased survivin expression, UCN-01 treatment did not increase X-linked inhibitor of apoptosis protein (XIAP) and survivin levels. Analysis of specific phosphoepitopes on chk1/2, Akt, and GSK3b following UCN-01 treatment determined that there was no significant change in phospho-chk1/2. However, there was decreased immunoreactivity at Ser473 and Thr308 of Akt and Ser9 of GSK3b by 4 h indicating that the Akt survival pathway and downstream signalling was compromised. Thus, UCN-01 was effective at inducing apoptosis in neuroblastoma cell lines. Keywords: Akt, apoptosis, GSK3b, neuroblastomas, staurosporine, survivin, 7-hydroxystaurosporine (UCN-01). Neuroblastoma is the most common malignancy of infancy and constitutes 50% of all childhood cancers (Gale et al. 1982;Young et al. 1986;Taylor and Locker 1990;Brodeur and Castleberry 1997). Some neuroblastomas may be cured by minimal therapy; however, there is no effective treatment for many advanced and metastatic neuroblastomas (Brodeur and Castleberry 1997). In addition, present treatments for neuroblastoma have significant morbidity (Brodeur and Castleberry 1997). Among the specific biological abnormalities that correlate with poor clinical outcome and aggressiveness of the tumor are nuclear DNA content, near diploidy or tetraploidy (Taylor et al. 1988;Taylor and Locker 1990;Gestblom et al. 1995), deletion of the short arm of chromosome 1 (1p) (Westermann and Schwab 2002), N-myc amplification (Taylor and Locker 1990), loss of Bcl-2 (Reed et al. 1991), insensitivity to radiation (Halperin et al. 1999), and increased expression of the inhibitor-of-apoptosis (IAP) family member, survivin (Adida et al. 1998;Azuhata et al. 2001). While these factors predict therapeutic outcome, there are specific biological determinants, such as components of the apoptotic cascade, that may be prognostic indicators for drug resistance (Emran et al. 2002;Gallo et al. 2003;Iolascon et al. 2003). Therefore, new and novel therapies with a biological rationale are urgently needed for this fatal disease.Members of the IAP family bind to and inhibit caspases and suppress cell death in cancer. Presently, there are eight mammalian IAP family members that include survivin, neuronal apoptosis inhibitor protein (NAIP), BIR-repeatcontaining ubiquitin-conjugating enzyme (BRUCE), livin, ILP-2, cIAP-1, cIAP-...

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“…Other transducing inhibitors, such as KN-62 and U-0126, for CaMKII and ERK-1,2 proteins, respectively, did not affect BzATP protective action, and also they did not have any significant effect by themselves. Moreover, cell death was almost totally rescued with the GSK-3 specific inhibitor, SB-216763 (Cross et al 2001) (Fig. 6b).…”

Section: Bzatp Protects Granule Neurons From Apoptosis Induced By Pi3mentioning

confidence: 93%

P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons

et al. 2009

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In this study we report the coupling of nucleotide receptors to GSK-3 signalling, a relevant survival pathway in cerebellar granule neurons. P2X 7 agonist BzATP induced a 3-4-fold increase in GSK-3 phosphorylation, which is reported to be associated with the catalytic activity inhibition. This effect was dependent on extracellular calcium and PKC, and independent of PI3-K (phosphatidyl-inositol-3-kinase)/Akt, the main survival route of neurotrophins. BzATP also prevented the apoptosis of granule neurons induced by the pharmacological inhibition of the PI3-K signalling. Both effects, BzATPmediated GSK-3 phosphorylation and neuroprotection, were abolished by P2X 7 receptor antagonists, BBG, PPADS and A-438079. We found that BzATP prevented the progressive GSK-3 dephosphorylation and caspase-3 activation occurring under conditions of sustained PI3-K inhibition. These results reveal that P2X 7 receptor activation could provide a relevant survival route alternative to classical neurotrophic factors.

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Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death

Cited by 345 publications

References 45 publications

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels

UCN‐01 alters phosphorylation of Akt and GSK3β and induces apoptosis in six independent human neuroblastoma cell lines

P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons

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