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GSK3β is a promising target for treating various disease conditions, including myocardial ischemia–reperfusion injury (IR). This study investigated the potential of GSK3β as a novel drug for managing IR in rats exposed to PM2.5 for 1 day and up to 21 days. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m3 for 3 h daily for either a single day or 21 days. After exposure, the isolated rat hearts underwent 30 min of ischemia followed by 60 min of reperfusion. GSK3β inhibition effectively reduced IR injury in rat hearts from animals exposed to PM2.5 for 1 day but not in those exposed for 21 days. PM2.5 exposure disrupted the redox balance in mitochondria and reduced the gene expression of antioxidants (glutaredoxin and peroxiredoxin) and NRF2, which protects against oxidative stress. PM2.5 also impaired mitochondrial bioenergetics, membrane potential, and quality control, leading to mitochondrial stress. Importantly, PM2.5 increased the translocation of GSK3β into mitochondria and compromised the overall mitochondrial function, particularly in the 21-day-exposed rat myocardium. The results indicate that extended exposure to PM2.5 leads to oxidative stress that disrupts mitochondrial function and diminishes the effectiveness of GSK3β inhibitors in offering cardio-protection through mitochondria. [ABSTRACT FROM AUTHOR]

Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3β inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3β signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3β may not be a reliable therapeutic target for IR in the presence of chronic PM2.5 exposure. [ABSTRACT FROM AUTHOR]

GSK3β is a promising target for treating various disease conditions, including myocardial ischemia–reperfusion injury (IR). This study investigated the potential of GSK3β as a novel drug for managing IR in rats exposed to PM2.5 for 1 day and up to 21 days. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m3 for 3 h daily for either a single day or 21 days. After exposure, the isolated rat hearts underwent 30 min of ischemia followed by 60 min of reperfusion. GSK3β inhibition effectively reduced IR injury in rat hearts from animals exposed to PM2.5 for 1 day but not in those exposed for 21 days. PM2.5 exposure disrupted the redox balance in mitochondria and reduced the gene expression of antioxidants (glutaredoxin and peroxiredoxin) and NRF2, which protects against oxidative stress. PM2.5 also impaired mitochondrial bioenergetics, membrane potential, and quality control, leading to mitochondrial stress. Importantly, PM2.5 increased the translocation of GSK3β into mitochondria and compromised the overall mitochondrial function, particularly in the 21-day-exposed rat myocardium. The results indicate that extended exposure to PM2.5 leads to oxidative stress that disrupts mitochondrial function and diminishes the effectiveness of GSK3β inhibitors in offering cardio-protection through mitochondria.

Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3β inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3β signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3β may not be a reliable therapeutic target for IR in the presence of chronic PM2.5 exposure.

Abstract Background Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by β-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/β-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR). Methods In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3β was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCHR8–5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCHR8–5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCHR8–5 cells. Results In this study, we observed that the components of Wnt/β-catenin pathway such as Wnt and GSK 3β were activated in multidrug resistant KBCHR8–5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3β in KBCHR8–5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCHR8–5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin-mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCHR8–5 cells. Conclusion The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/β-catenin signaling in drug-resistant KBCHR8–5 cells.

Purpose: 6-Gingerol, a major biochemical and pharmacological active ingredient of ginger, has shown anti-inflammatory and antitumor activities against various cancers. Searching for natural products with fewer side effects for developing adjunctive therapeutic options is necessary.Methods: The effects of 6-gingerol on proliferation, colony formation, and cell cycle in RCC cells were detected by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and propidium iodide (PI) staining, respectively. Western blotting, an immunofluorescence assay, and immunohistochemical staining were performed to assess the expression of relevant proteins. A subcutaneous tumor model was set up to investigate the 6-gingerol effects on tumor growth in vivo, and the pharmacokinetics of 6-gingerol in mice were detected by LC/MS assays.Results: 6-Gingerol treatment exerted time- and dose-dependent inhibition of the growth and colony formation of ACHN, 786-O, and 769-P cells, leading to a concomitant induction of cell-cycle G1-phase arrest and decrease in Ki-67 expression in the cell nucleus. Western-blotting results showed that 6-gingerol reduces phosphorylation of protein kinase B (AKT) Ser 473, cyclin-dependent kinases (CDK4), and cyclin D1 and, meanwhile, increases glycogen synthase kinase (GSK 3β) protein amount. Furthermore, the efficacy of 6-gingerol was demonstrated in an in vivo murine model of 786-O.Conclusion: The above results indicate that 6-gingerol can induce cell-cycle arrest and cell-growth inhibition through the AKT-GSK 3β-cyclin D1 signaling pathway in vitro and in vivo, suggesting that 6-gingerol should be useful for renal-cell carcinoma treatment. [ABSTRACT FROM AUTHOR]

Background: Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by β-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/β-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR). Methods: In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3β was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCHR8–5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCHR8–5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCHR8–5 cells. Results: In this study, we observed that the components of Wnt/β-catenin pathway such as Wnt and GSK 3β were activated in multidrug resistant KBCHR8–5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3β in KBCHR8–5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCHR8–5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin-mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCHR8–5 cells. Conclusion: The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/β-catenin signaling in drug-resistant KBCHR8–5 cells. [ABSTRACT FROM AUTHOR]

Background: Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by β-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/β-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR).Methods: In this study, we screened selected flavonoids against Wnt/β-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3β was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCHR8-5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCHR8-5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCHR8-5 cells.Results: In this study, we observed that the components of Wnt/β-catenin pathway such as Wnt and GSK 3β were activated in multidrug resistant KBCHR8-5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3β in KBCHR8-5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCHR8-5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin-mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCHR8-5 cells.Conclusion: The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/β-catenin signaling in drug-resistant KBCHR8-5 cells. [ABSTRACT FROM AUTHOR]

The development of targeted tyrosine kinase inhibitors (TKIs) has succeeded in altering the course of chronic myeloid leukemia (CML). However, a number of patients have failed to respond or experienced disease relapse following TKI treatment. Proviral integration site for moloney murine leukemia virus‑1 (PIM‑1) is a serine/threonine kinase that participates in regulating apoptosis, cell cycle, signal transduction and transcriptional pathways, which are associated with tumor progression, and poor prognosis. SMI‑4a is a selective PIM‑1 kinase inhibitor that inhibits PIM‑1 kinase activity in vivo and in vitro. The present study aimed to explore the mechanism underlying the antitumor effect of SMI‑4a in K562 and imatinib‑resistant K562 (K562/G) cell lines. It was demonstrated that SMI‑4a inhibited the proliferation of K562 and K562/G cells using a WST‑8 assay. The Annexin V‑propidium iodide assay demonstrated that SMI‑4a induced apoptosis of K562 and K562/G cells in a dose‑, and time‑dependent manner. Furthermore, Hoechst 33342 staining was used to verify the apoptosis rate. The clone formation assay revealed that SMI‑4a significantly inhibited the colony formation capacity of K562 and K562/G cells. Western blot analysis demonstrated that SMI‑4a decreased phosphorylated (p)‑Ser9‑glycogen synthase kinase (GSK) 3β/pGSK3β and inhibited the translocation of β‑catenin. In addition, the downstream gene expression of apoptosis regulator Bax and poly(ADP‑ribose) polymerase‑1 was upregulated, and apoptosis regulator Bcl‑2 and Myc proto‑oncogene protein expression levels were downregulated. Immunofluorescence results demonstrated changes in the expression level of β‑catenin in the plasma and nucleus. The results of the present study suggest that SMI‑4a is an effective drug to use in combination with current chemotherapeutics for the treatment of imatinib‑resistant CML. [ABSTRACT FROM AUTHOR]

Recent studies suggest that genetic factors contribute to the pathogenesis of sporadic Alzheimer's disease (sAD). Glycogen synthase kinase-3 beta (GSK 3β) is an important molecule which regulates tau phosphorylation and neurofibrillary tangles formation. GSK 3β gene may be a potential candidate gene for the risk of sAD. To investigate the association of the polymorphisms in GSK 3β gene with sAD, we conducted a case-control study in a southern Chinese Han cohort including 302 sAD patients and 315 control participants. Four single nucleotide polymorphisms (SNPs) (rs3732361, rs56728675, rs60393216, and rs334558) within the promoter region of GSK 3β gene were selected and genotyped with a polymerase chain reaction-ligase detection (PCR-LDR) method. Logistic regression was used to analyze the association between target SNPs and the risk of sAD. After adjusting for age, sex, and APOE ε4 status, no association was revealed between these SNPs and sAD ( P > 0.05). The SNPs in the selected regions of GSK 3β gene are unlikely to confer the susceptibility of sAD in southern Chinese Han population. Further studies with a larger sample size and different ethnic populations are needed to reveal the role of SNPs of GSK 3β gene in the pathogenesis of sAD. [ABSTRACT FROM AUTHOR]

Abstract: Artemisinin and its derivatives (ARTs) are effective antimalarial drugs and also possess profound anticancer activity. However, the mechanism accounted for its distinctive activity in tumor cells remains unelucidated. We computed Pair wise Pearson correlation coefficients to identify genes that show significant correlation with ARTs activity in NCI-55 cell lines using data obtained from studies with HG-U133A Affymetrix chip. We found c-myc is one of the genes that showed the highest positive correlation coefficients among the probe sets analyzed (r =0.585, P <0.001). Dihydroartemisinin (DHA), the main active metabolite of ARTs, induced significant apoptosis in HL-60 and HCT116 cells that express high levels of c-MYC. Stable knockdown of c-myc abrogated DHA-induced apoptosis in HCT116 cells. Conversely, forced expression of c-myc in NIH3T3 cells sensitized these cells to DHA-induced apoptosis. Interestingly, DHA irreversibly down-regulated the protein level of c-MYC in DHA-sensitive HCT116 cells, which is consistent to persistent G1 phase arrest induced by DHA. Further studies demonstrated that DHA accelerated the degradation of c-MYC protein and this process was blocked by pretreatment with the proteasome inhibitor MG-132 or GSK 3β inhibitor LiCl in HCT116 cells. Taken together, ARTs might be useful in the treatment of c-MYC-overexpressing tumors. We also suggest that c-MYC may potentially be a biomarker candidate for prediction of the antitumor efficacies of ARTs. [Copyright &y& Elsevier]

The canonical Wnt/β-catenin pathway is a highly conserved signaling cascade that is involved in development and stem cell renewal. The deregulation of this pathway is often associated with increased cell growth and neoplasia. The small GTPase Rac has been shown to influence canonical Wnt signaling by regulating β-catenin stability through an unknown mechanism. We report that DOCK4, a guanine nucleotide exchange factor (GEF) for Rac and a member of the CDM family of unconventional GEFs, mediates Wnt-induced Rac activation in the canonical Wnt/β-catenin pathway. DOCK4 expression regulates cellular β-catenin levels in response to the Wnt signal, in vitro. Biochemical studies demonstrate that DOCK4 interacts with the β-catenin degradation complex, consisting of the proteins adenomatosis polyposis coli, Axin and glycogen synthase kinase 3β (GSK3β). This molecular interaction enhances β-catenin stability and Axin degradation. Furthermore, we observe that DOCK4 is phosphorylated by GSK3β, which enhances Wnt-induced Rac activation. Using a T-cell factor reporter zebrafish we confirm that DOCK4 is required for Wnt/β-catenin activity, in vivo. These results elucidate a novel intracellular signaling mechanism in which a Rac GEF, DOCK4 acts as a scaffold protein in the Wnt/β-catenin pathway.Oncogene (2008) 27, 5845–5855; doi:10.1038/onc.2008.202; published online 21 July 2008 [ABSTRACT FROM AUTHOR]

Abstract: Dephosphorylated and activated glycogen synthase kinase (GSK) 3β hyperphosphorylates β-catenin, leading to its ubiquitin-proteosome-mediated degradation. β-catenin-knockdown increases while β-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of β-catenin are reduced in the brain of Alzheimer''s patients. However, whether β-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK 3β and β-catenin, and the protective effect of moderate hypothermia (30 °C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK 3β was dephosphorylated at 5 and 24 h after stroke in the normothermic (37 °C) brain; hypothermia augmented GSK 3β dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK 3β dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK 3β protein. Corresponding to GSK 3β activity in normothermic rats, β-catenin phosphorylation transiently increased at 5 h in both the ischemic penumbra and core, and the total protein level of β-catenin degraded after normothermic stroke. Hypothermia did not inhibit β-catenin phosphorylation, but it blocked β-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize β-catenin, which may contribute to the protective effect of moderate hypothermia. [Copyright &y& Elsevier]

Although lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder, the mechanisms underlying its therapeutic action are still unclear. Together with its mood-stabilizing effects, lithium is also known to influence the circadian clocks of several organisms including man. Circadian rhythms are altered in patients with bipolar disorder, and it is believed that these rhythms may play an important role in disease mechanisms. It is therefore possible that some of the therapeutic actions of lithium may be related to its effect on circadian clocks. Identifying the targets for lithium's action on circadian clocks would therefore be important both for understanding the mechanisms of its therapeutic effect and also in further understanding disease mechanisms in bipolar disorders. Using Drosophila melanogaster as a model system, we show that long-term administration of lithium results in lengthening of the free-running period (τ) of circadian locomotor activity rhythm of flies in constant darkness (DD). This effect occurs at concentrations similar to the plasma levels of lithium used in the treatment of bipolar disorder. The lithium-treated flies also show reduced activity of one of the previously reported targets of lithium action, Glycogen Synthase Kinase 3β (GSK 3β). GSK 3β has been shown to be involved in the regulation of circadian clocks as the down regulation of this protein results in an elongation of τ. The τ elongation resembles the effect seen with lithium administration in a number of organisms including man, and taken together with the earlier observations our results suggest that lithium inhibits the activity of GSK 3β to produce its effect on circadian clocks. [ABSTRACT FROM AUTHOR]

To investigate the role of Skp2 and JunB on acute promyelocytic leukemia (APL) progression and the related mechanism. The expression of Skp2 in NB4 cell line was depleted to explore its effect on proliferation and differentiation both in vitro and in vivo assays. Western blot and quantitative RT-PCR analysis were performed to explore Skp2-regulated downstream target genes. Luciferase and co-immunoprecipitation analysis indicated that PML-RARα inhibited the transactivation of JunB by interacting with the PU.1 protein. The western blot analysis confirmed that Skp2 could maintain the stability of PML-RARα. We report that the progression of APL and the attenuation of APL sensitivity to ATRA are positively associated with Skp2. Elevated Skp2 expression promotes APL progression by decreasing the expression of lncRNA HOTAIRM1 and inactivation of GSK3β, causing autophagy inhibition followed by the suppression of PML-RARα ubiquitylation and degradation, which represses JunB transcriptional activation through PU.1/PML-RARα transcriptional complex to block cell differentiation. Coupled with ATRA or GSK3β inhibitor treatment, genetic or pharmacological inhibition of Skp2 strikingly induces JunB expression by accelerating the degradation of PML-RARα, which contributes to the eradication of APL. Additionally, the expressions of Skp2 and JunB are negatively correlated in mice subcutaneous leukemia xenograft tumors. Collectively, this study uncovers the roles of Skp2 in PML-RARα stabilization and in APL oncogenic functions. We reveal a novel mechanism of PML-RARα degradation and JunB regulation that constitute an important signaling network of Skp2-GSK3β-PML/RARα-JunB. • High Skp2 expression promotes APL progression and correlation negatively with JunB expression in APL. • Skp2 maintains the stability of PML-RARα through inhibiting lncRNA HOTAIRM1-associated autophagy. • PML-RARα suppresses JunB transactivation through PU.1 binding site. • Skp2 regulates PML-RARα and JunB expression through AKT/GSK3β pathway. [ABSTRACT FROM AUTHOR]

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±) -BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±) -BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.

Modification of the Small Ubiquitin-like Modifier (SUMO) (SUMOylation) appears to regulate diverse cellular processes, including nuclear transport, signal transduction, apoptosis, autophagy, cell cycle control, ubiquitin-dependent degradation and gene transcription. Glycogen synthase kinase 3beta (GSK 3beta) is a serine/threonine kinase that is thought to contribute to a variety of biological events, including embryonic development, metabolism, tumorigenesis, and cell death. GSK 3beta is a constitutively active kinase that regulates many intracellular signaling pathways by phosphorylating substrates such as beta-catenin. We noticed that the putative SUMOylation sites are localized on K(292 )residueof (291)FKFPQ(295) in GSK 3beta based on analysis of the SUMOylation consensus sequence. In this report, we showed that the SUMOylation of GSK 3beta occurs on its K(292) residue, and this modification promotes its nuclear localization in COS-1. Additionally, our data showed that the GSK 3beta SUMO mutant (K292R) decreased its kinase activity and protein stability, affecting cell death. Therefore, our observations at first time suggested that SUMOylation on the K(292) residue of GSK 3beta might be a GSK 3beta regulation mechanism for its kinase activation, subcellular localization, protein stability, and cell apoptosis.