αB-crystallin Gene Induction and Phosphorylation by MKK6-activated p38

Hoover, Holly; Thuerauf, Donna J.; Martindale, Joshua J.; Glembotski, Christopher C.

doi:10.1074/jbc.m003864200

Cited by 137 publications

(58 citation statements)

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“…MKK6 overexpression leads to increased ␣BC expression in cultured cardiac myocytes (28), and ␣BC overexpression has been shown to protect stressed cardiac myocytes in vitro (37) and stressed hearts in vivo (29,34). Although it is not known how ␣BC exerts these protective effects in the heart, in many cell types ␣BC is known to reduce apoptosis (29,37,38), which is responsible for a portion of I/R-induced myocardial damage (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Essentially no Bcl-2 was found in cytosolic fractions, consistent with the constitutive mitochondrial localization of this protein (41). small heat shock protein, ␣B-crystallin (␣BC), in cultured cardiac myocytes (28). Moreover, transgenic mice that overexpress ␣BC in the heart exhibit myocardial protection from I/R (34), whereas the hearts from mice in which ␣BC expression has been disrupted are more susceptible to I/R-induced damage (29).…”

Section: Fig 5 Effects Of Mkk6 Overexpression On ␣Bc and Bcl-2mentioning

confidence: 99%

“…FLAG Western Analysis and Immunoprecipitation Kinase Assays-FLAG-related material was immunoprecipitated from cardiac extracts and assessed for the ability to phosphorylate the kinase-inactive MKK6-specific substrate, p38␤(K53R), 2 as previously described (28).…”

Section: Table II Body and Left Ventricle Weightsmentioning

confidence: 99%

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Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

Martindale

Wall

Martinez-Longoria

et al. 2005

Journal of Biological Chemistry

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The mitogen-activated protein kinases (MAPK) have been the subject of many studies to identify signaling pathways that promote cell survival or death. In cultured cardiac myocytes, p38 MAPK promotes cell survival or death depending on whether it is activated by mitogen-activated protein kinase kinase 6 (MKK6) or MKK3, respectively. The objectives of the current study were to examine the effects of MKK6-mediated p38 activation in the heart in vivo. Accordingly, we generated transgenic (TG) mice that overexpress wild type MKK6 in a cardiac-restricted manner. Although p38 was about 17-fold more active in TG than non-transgenic (NTG) mouse hearts, TG mouse hearts were morphologically and functionally similar to those of NTG littermates. However, upon transient ischemia followed by reperfusion, the MKK6 TG mouse hearts exhibited significantly better functional recovery and less injury than NTG mouse hearts. Because MKK6 increases levels of the protective small heat shock protein, ␣B-crystallin (␣BC), in cultured cardiac myocytes, we examined ␣BC levels in the mouse hearts. The level of ␣BC was 2-fold higher in MKK6 TG than NTG mouse hearts. Moreover, ischemia followed by reperfusion induced a 6.4-fold increase in ␣BC levels in the mitochondrial fractions of TG mouse hearts but no increase in ␣BC levels in any of the other fractions analyzed. These alterations in ␣BC expression and localization suggest possible mechanisms of cardioprotection in MKK6 TG mouse hearts.

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Section: Discussionmentioning

confidence: 99%

Section: Fig 5 Effects Of Mkk6 Overexpression On ␣Bc and Bcl-2mentioning

confidence: 99%

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Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

Martindale

Wall

Martinez-Longoria

et al. 2005

Journal of Biological Chemistry

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“…␣B-crystallin has three phosphorylation sites. Serine 59 is phosphorylated when cells are stressed, and serines 19 and 45 are found phosphorylated when cells are going into mitosis (11,12). The overall level of phosphorylation of ␣B-crystallin remains low (13).…”

mentioning

confidence: 94%

Translational Thermotolerance Provided by Small Heat Shock Proteins Is Limited to Cap-dependent Initiation and Inhibited by 2-Aminopurine

Doerwald

Onnekink

Genesen

et al. 2003

Journal of Biological Chemistry

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Heat shock results in inhibition of general protein synthesis. In thermotolerant cells, protein synthesis is still rapidly inhibited by heat stress, but protein synthesis recovers faster than in naive heat-shocked cells, a phenomenon known as translational thermotolerance. Here we investigate the effect of overexpressing a single heat shock protein on cap-dependent and cap-independent initiation of translation during recovery from a heat shock. When overexpressing ␣B-crystallin or Hsp27, cap-dependent initiation of translation was protected but no effect was seen on cap-independent initiation of translation. When Hsp70 was overexpressed however, both cap-dependent and -independent translation were protected. This finding indicates a difference in the mechanism of protection mediated by small or large heat shock proteins. Phosphorylation of ␣B-crystallin and Hsp27 is known to significantly decrease their chaperone activity; therefore, we tested phosphorylation mutants of these proteins in this system. ␣B-crystallin needs to be in its non-phosphorylated state to give protection, whereas phosphorylated Hsp27 is more potent in protection than the unphosphorylatable form. This indicates that chaperone activity is not a prerequisite for protection of translation by small heat shock proteins after heat shock. Furthermore, we show that in the presence of 2-aminopurine, an inhibitor of kinases, among which is double-stranded RNA-activated kinase, the protective effect of overexpressing ␣B-crystallin is abolished. The synthesis of the endogenous Hsps induced by the heat shock to test for thermotolerance is also blocked by 2-aminopurine. Most likely the protective effect of ␣B-crystallin requires synthesis of the endogenous heat shock proteins. Translational thermotolerance would then be a co-operative effect of different heat shock proteins.

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“…Activated p38 MAPK phosphorylates nuclear MK2 and forms a complex whereby an MK2 nuclear export signal is unmasked, resulting in its rapid export from the nucleus (Maulik et al 1996;Engel et al 1995;Ben Levy et al 1998). In the cytoplasm, MK2 phosphorylates the small heat shock proteins (HSP) 25/27 (Stokoe et al 1992;Freshney et al 1994;Rouse et al 1994) and αB-crystallin (Hoover et al 2000;Ito et al 2001;Kato et al 1998). The phosphorylation of HSP25/27 induces its dissociation from large aggregates into dimers and monomers (Kato et al 1994).…”

Section: Introductionmentioning

confidence: 99%

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

Gorog¹,

Jabr²,

Tanno³

et al. 2009

Cell Stress and Chaperones

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MAPKAPK-2 (MK2) is a protein kinase activated downstream of p38-MAPK which phosphorylates the small heat shock proteins HSP27 and αB crystallin and modulates p38-MAPK cellular distribution. p38-MAPK activation is thought to contribute to myocardial ischemic injury; therefore, we investigated MK2 effects on ischemic injury and p38 cellular localization using MK2-deficient mice (KO). Immunoblotting of extracts from Langendorffperfused hearts subjected to aerobic perfusion or global ischemia or reperfusion showed that the total and phosphorylated p38 levels were significantly lower in MK2 −/− compared to MK2 +/+ hearts at baseline, but the ratio of phosphorylated/total p38 was similar. These results were confirmed by cellular fractionation and immunoblotting for both cytosolic and nuclear compartments. Furthermore, HSP27 and αB crsytallin phosphorylation were reduced to baseline in MK2 −/− hearts. On semiquantitative immunofluorescence laser confocal microscopy of hearts during aerobic perfusion, the mean total p38 fluorescence was significantly higher in the nuclear compared to extranuclear (cytoplasmic, sarcomeric, and sarcolemmal compartments) in MK2 +/+ hearts. However, although the increase in phosphorylated p38 fluorescence intensity in all compartments following ischemia in MK2 +/+ hearts was lost in MK2 −/− hearts, it was basally elevated in nuclei of MK2 −/− hearts and was similar to that seen during ischemia in MK2 +/+ hearts. Despite these differences, similar infarct volumes were recorded in wild-type MK2 +/+ and MK2 −/− hearts, which were decreased by the p38 inhibitor SB203580 (1 μM) in both genotypes. In conclusion, p38 MAPKinduced myocardial ischemic injury is not modulated by MK2. However, the absence of MK2 perturbs the cellular distribution of p38. The preserved nuclear distribution of active p38 MAPK in MK2 −/− hearts and the conserved

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αB-crystallin Gene Induction and Phosphorylation by MKK6-activated p38

Cited by 137 publications

References 59 publications

Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo

Translational Thermotolerance Provided by Small Heat Shock Proteins Is Limited to Cap-dependent Initiation and Inhibited by 2-Aminopurine

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

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