Heat Shock Protein 27 Controls Apoptosis by Regulating Akt Activation

Rane, Madhavi J.; Pan, Yong; Singh, Saurabh; Powell, David W.; Wu, Rui; Cummins, Timothy D.; Chen, Qingdan; McLeish, Kenneth R.; Klein, Jon B.

doi:10.1074/jbc.m303417200

Cited by 337 publications

(330 citation statements)

References 44 publications

(64 reference statements)

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“…Of the kinases shown to catalyze the phosphorylation of hsp27, PKC is lipid-dependent and the experiments conducted herein were performed without lipid and in the presence of EGTA plus a peptide inhibitor of PKA (PKI, 1 μM); hence, these kinases would not be active. PKB forms a complex with [50] and phosphorylates hsp27 [41,42]. However, activated PKB requires higher [NaCl] to elute from Mono Q than observed for the hsp27 kinase activities reported herein.…”

Section: Discussioncontrasting

confidence: 40%

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Characterization of hsp27 kinases activated by elevated aortic pressure in heart

et al. 2012

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Chronic hemodynamic overload results in left ventricular hypertrophy, fibroblast proliferation, and interstitial fibrosis. The small heat shock protein hsp27 has been shown to be cardioprotective and this requires a phosphorylatable form of this protein. To further understand the regulation of hsp27 in heart in response to stress, we investigated the ability of elevated aortic pressure to activate hsp27-kinase activities. Isolated hearts were subjected to retrograde perfusion and then snapfrozen. Hsp27-kinase activity was measured in vitro as hsp27 phosphorylation. Immune complex assays revealed that MK2 activity was low in non-perfused hearts and increased following crystalline perfusion at 60 or 120 mmHg. Hsp27-kinase activities were further studied following ion-exchange chromatography. Anion exchange chromatography on Mono Q revealed 2 peaks ('b' and 'c') of hsp27-kinase activity. A third peak 'a' was detected upon chromatography of the Mono Q flow-through fractions on the cation exchange resin, Mono S. The hsp27-kinase activity underlying peaks 'a' and 'c' increased as perfusion pressure was increased from 40 to 120 mmHg. In contrast, peak 'b' increased over pressures 60-100 mmHg but was decreased at 120 mmHg. Peaks 'a', 'b', and 'c' contained MK2 immunoreactivity, whereas MK3 and MK5 immunoreactivity was detected in peak 'a'. p38 MAPK and phospho-p38 MAPK were also detected in peaks 'b' and 'c' but absent from peak 'a'. Hsp27-kinase activity in peaks 'b' and 'c' (120 mmHg) eluted from a Superose 12 gel filtration column with an apparent molecular mass of 50-kDa. Hence, peaks 'b' and 'c' were not a result of MK2 forming complexes. In-gel hsp27-kinase assays revealed a single 49-kDa renaturable hsp27-kinase activity in peaks 'b' and 'c' at 60 mmHg, whereas several hsp27-kinases (p43, p49, p54, p66) were detected in peaks 'b' and 'c' from hearts perfused at 120 mmHg. Thus, multiple hsp27-kinases were activated in response to elevated aortic pressure in isolated, perfused rat hearts and hence may be implicated in regulating the cardioprotective effects of hsp27 and thus may represent targets for cardioprotective therapy.

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Section: Discussioncontrasting

confidence: 40%

“…Hsp27 is phosphorylated by several protein kinases, including PKA [40], PKB [41,42], PKC [40,43], PKD [44], PKG [45], MK2 [46], MK3 [47], and MK5/PRAK [48,49] in vitro ( Fig. 1, reviewed in [8]).…”

Section: Discussionmentioning

confidence: 99%

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

et al. 2012

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“…In addition, Hsp27 acts early during cell stress to stabilize and accelerate the recovery of actin filaments, thus preventing the disruption of the cytoskeleton (34). Hsp27 is also involved in the regulation of the serine/ threonine kinase AKT (protein kinase B), an important signaling molecule for cell survival and proliferation (35). Hsp27 can exert its antiapoptotic effects through the enhancement of nuclear factor-nB activity, by facilitating proteasomal degradation of its main inhibitor I-nB (36).…”

Section: Discussionmentioning

confidence: 99%

Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells

Kamada

Muramaki

et al. 2007

Molecular Cancer Therapeutics

171

136

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“…Furthermore, phosphorylation of Hsp27 by Akt results in its dissociation from Akt and may participate to the Hsp27-induced delay in PMN apoptosis (31). We therefore studied the effects of TLR agonists on Hsp27 phosphorylation by means of flow cytometry.…”

Section: Pi3k/akt Dependence Of Tlr Agonist Action On Pmn Apoptosismentioning

confidence: 99%

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

François

Benna

Dang

et al. 2005

The Journal of Immunology

206

223

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Using flow cytometry, we investigated the effect of TLR agonists on human polymorphonuclear neutrophil (PMN) apoptosis in whole blood. LPS (TLR4), peptidoglycan (TLR2), R-848 (TLR7/8), and CpG-DNA (TLR9) were equally effective at delaying spontaneous apoptosis of PMN, while PamCSK4 (TLR1/2), macrophage-activating lipopeptide-2 (TLR2/6), flagellin (TLR5), and loxoribine (TLR7) were less effective or inactive. TLR agonists found to delay apoptosis also extended the functional life span of PMN. Analysis of signaling pathways revealed that the antiapoptotic effect of TLR agonists required NF-κB and PI3K activation. Furthermore, analysis of intact cells by flow cytometry showed that TLR agonists delaying PMN apoptosis increased phosphorylation of Akt, a major target of PI3K. This effect was associated with a PI3K-dependent increase in heat shock protein 27 phosphorylation, which has been reported to play a key role in PMN survival. Finally, the TLR-induced delay in PMN apoptosis was associated with increased levels of Mcl-1 and A1, which are antiapoptotic members of the Bcl-2 family. These effects were reversed by PI3K and NF-κB inhibitors, respectively. TLR activation also led to PI3K-dependent phosphorylation of the proapoptotic protein Bad. Taken together, our results strongly suggest a role of NF-κB and PI3K in TLR-induced PMN survival, leading to modulation of Bcl-2 family molecules.

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Heat Shock Protein 27 Controls Apoptosis by Regulating Akt Activation

Cited by 337 publications

References 44 publications

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

Characterization of hsp27 kinases activated by elevated aortic pressure in heart

Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-κB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

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