Glycogen synthase kinases 3α and 3β in cardiac myocytes: Regulation and consequences of their inhibition

Markou, Thomais; Cullingford, Timothy E.; Giraldo, Alejandro; Weiss, Sophie C.; Alsafi, Ali; Fuller, Stephen J.; Clerk, Angela; Sugden, Peter H.

doi:10.1016/j.cellsig.2007.10.004

Cited by 55 publications

(52 citation statements)

References 84 publications

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“…The most notable difference between the 2 isoforms is that GSK-3␣ possesses a glycine-rich N-terminal extension of unknown function that is absent in GSK-3␤, resulting in 5-kDa difference in molecular mass between isoforms. 31 However, the isoforms share more than 98% homology within their kinase domain, 19 seem approximately equally abundant in cardiac myocytes, 32 in keeping with our findings, are identically inhibited by PKB/ Akt, 31 cannot be selectively inhibited pharmacologically, 31 and, most importantly, exhibit functional redundancy on systematic allelic disruption. 31 Thus, although the emphasis to date has been on GSK-3␤, it seems probable that inhibition of GSK-3␣ could similarly lead to protection or even that coincident inhibition of both kinases is required.…”

Section: Discussionsupporting

confidence: 73%

Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse

Nishino

Webb

Davidson

et al. 2008

Circulation Research

114

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Abstract-The inactivation of glycogen synthase kinase-3␤ (GSK-3␤) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3␤ (Ser9) and the highly homologous GSK-3␣ (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse. (Circ Res. 2008;103:307-314.)Key Words: postconditioniong Ⅲ preconditioning Ⅲ GSK-3 Ⅲ mPTP I schemic preconditioning is a powerful and established modulator of intrinsic myocardial resistance to lethal ischemia. 1 Its clinical application in patients with acute myocardial infarction is limited as a result of the inability to predict the moment of coronary artery occlusion. More recently, Zhao et al described the concept of postconditioning as a novel strategy for protecting the heart against reperfusion-injury. 2 They demonstrated that a similar regimen of brief periods of ischemia after a lethal index ischemic insult was as protective as preconditioning. This phenomenon has subsequently been confirmed in a variety of animal models, both in vivo and in isolated heart preparations, 3 as well as in preliminary clinical interventional studies. 4,5 The endogenous cellular and molecular mechanisms involved in cardioprotection against ischemia have been extensively investigated in the field of preconditioning. 6 Because pre-and postconditioning are temporally remote, the signaling pathways might be expected to differ considerably. 2,7 However, recent evidence suggests that the early reperfusion phase after lethal ischemia is crucial i...

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Section: Discussionsupporting

confidence: 73%

Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse

Nishino

Webb

Davidson

et al. 2008

Circulation Research

114

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“…Gsk3b is a negative regulator of heart hypertrophy. 33 Interestingly, Hauck 34 recently described that silencing p27 induced cardiomyocyte hypertrophyc growth in the absence of growth-factor stimulation. It is interesting to speculate that Gsk3b mediates negative regulation of hypertrophyc growth through its effects on p27 expression levels.…”

Section: Discussionmentioning

confidence: 99%

c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity

Quintavalle

Incoronato²,

Puca

et al. 2010

Cell Death Differ

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Akt is a serine-threonine kinase that has an important role in transducing survival signals. Akt also regulates a number of proteins involved in the apoptotic process. To find new Akt interactors, we performed a two-hybrid screening in yeast using full-length Akt cDNA as bait and a human cDNA heart library as prey. Among 200 clones obtained, two of them were identified as coding for the c-FLIP L protein. c-FLIP L is an endogenous inhibitor of death receptor-induced apoptosis through the caspase-8 pathway. Using co-immunoprecipitation experiments of either transfected or endogenous proteins, we confirmed the interaction between Akt and c-FLIP L . Furthermore, we observed that c-FLIP L overexpression interferes with Gsk3-b phosphorylation levels. Moreover, through its effects on Gsk3b, c-FLIP L overexpression in cancer cells induced resistance to tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL). This effect was mediated by the regulation of p27 Kip1 and caspase-3 expression. These results indicate the existence of a new mechanism of resistance to TRAIL in cancer cells, and unexpected functions of c-FLIP L .

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“…Among the transcription factors, the AP-1 family and FOXOs are the 2 types of being identified as typical regulators of skeletal muscle development. An AP-1 factor might play an important role in the maintenance of muscle mass, and the decrease in its transcriptional activity might contribute to the loss of muscle mass in atrophic conditions (Lecker et al, 2004;Sacheck et al, 2007;Markou et al, 2008;Avouac et al, 2012). FOXOs belong to the FOX (Forkhead box) family of transcription factors.…”

Section: Characteristics Of the Duck Mustn1 Genementioning

confidence: 99%

Characterization of MUSTN1 gene and its relationship with skeletal muscle development at postnatal stages in Pekin ducks

Xu¹,

Gu²,

Sun³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Musculoskeletal embryonic nuclear protein 1 (MUSTN1) gene is involved in myogenic fusion and differentiation in rats. We previously showed the differential expression of MUSTN1 in week (W) 2 and W6 breast muscles of Pekin ducks. In this study, we further investigated its molecular characteristics and expression profiles in different tissues at W7 and in breast and leg muscles at W1, W3, W5, W7, and W9. The relationship between muscle development and MUSTN1 and skeletal muscle development muscle fiber areas was also investigated. A 358-bp cDNA sequence was obtained. The coding sequence of duck MUSTN1 cDNA encoded a 78-amino acid sequence, which showed high similarity with those of other species (96% similarity with zebra finch and 94% with chicken). In addition, a 6435-bp genomic DNA sequence of MUSTN1 was obtained. In total, 231 transcription factor-binding sites were found in the promoter region, and many of these transcription factors were involved in the regulation of muscle development. MUSTN1 expression in breast muscle increased from W1 to W5 and then decreased at W9. In leg muscle, the expression increased from W1 to W3 and then decreased. The relative growth rates of breast and leg muscle fibers reached their peaks at W3-W5 and W1-W3, respectively. Since the greatest relative growth rates appeared at the highest expression levels of the MUSTN1 gene, it was thought to play roles in duck muscle development. Our findings would be helpful in understanding the molecular characteristics and functions of the MUSTN1 gene in breast muscle development of ducks.

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Glycogen synthase kinases 3α and 3β in cardiac myocytes: Regulation and consequences of their inhibition

Cited by 55 publications

References 84 publications

Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse

Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse

c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity

Characterization of MUSTN1 gene and its relationship with skeletal muscle development at postnatal stages in Pekin ducks

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