Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation

Costa, Romain Da; Almeida, Steven De; Chevarin, Martin; Hadj‐Rabia, S.; Leclerc‐Mercier, Stéphanie; Thauvin‐Robinet, Christel; Garrido, Carmen; Faivre, Laurence; Vabres, P.; Duplomb, Laurence

doi:10.1016/j.bbrc.2020.04.146

Cited by 13 publications

(6 citation statements)

References 37 publications

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“…However, AKT1 appeared to be a more potent inducer of HSF1 activity that likely stems from its ability to phosphorylate an additional three residues identified here that all functionally promote HSF1 activation. The PI3K pathway has been linked to HSF1 activity as far back as 2000 (59,77) but whether this was an indirect regulation or a direct regulation was unclear until our previous study indicating AKT1 directly activates HSF1 (15). The current study indicates that AKT1 also participates in heat stress-induced activation of HSF1 (Fig 2 ) and that AKT1-mediated activation is independent of mTORC1 (Fig 1).…”

Section: Discussionmentioning

confidence: 56%

“…However, AKT1 appeared to be a more potent inducer of HSF1 activity that likely stems from its ability to phosphorylate an additional three residues identified here that functionally promote HSF1 activation. The PI3K pathway has been linked to HSF1 activity as far back as 2000 (63,64) but whether this was an indirect regulation or a direct regulation was unclear until our previous study indicating AKT1 directly activates HSF1 (15). Collectively, this study indicates for the first time the functional role in HSF1induced transcription for these phosphorylation events by enhancing trimerization and gene transactivation and AKT1 targeting these residues likely explains its ability to promote higher levels of HSF1 activity.…”

Section: Discussionmentioning

confidence: 76%

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AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

Omari

Ray

et al. 2020

Preprint

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The heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activity requires nuclear localization, trimerization, DNA binding, phosphorylation, and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, and MEK1. mTOR, p38, and MEK1 all phosphorylated S326 but AKT1 was the more potent activator. Mass spectrometry showed that AKT1 phosphorylated HSF1 at T142, S230, and T527 in addition to S326 whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. This study suggests that HSF1 activity is regulated by phosphorylation at specific residues that promote different stages of HSF1 activation. Furthermore, this is the first study to identify the functional role of these phosphorylation events.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 76%

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

Omari

Ray

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, AKT1 appeared to be a more potent inducer of HSF1 activity that likely stems from its ability to phosphorylate an additional three residues identified here that all functionally promote HSF1 activation. The PI3K pathway has been linked to HSF1 activity as far back as 2000 [ 50 , 73 ] but whether this was an indirect regulation or a direct regulation was unclear until our previous study indicating AKT1 directly activates HSF1 [ 15 ]. The current study indicates that AKT1 also participates in heat stress-induced activation of HSF1 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

Omari

Ray

et al. 2022

The FEBS Journal

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The heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activation requires nuclear localization, trimerization, DNA binding, phosphorylation and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, MEK1 and DYRK2. Here, we observed activation of HSF1 by AKT1 independently of mTOR. AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1. Similarly, mTOR, p38, MEK1 and DYRK2 all phosphorylated S326 but AKT1 was the most potent activator. Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. Interestingly, T527 as a phosphorylated residue has not been previously shown and sits in the transactivation domain, further implying a role for this site in HSF1 gene transactivation. This study suggests that HSF1 hyperphosphorylation is targeted and these specific residues have direct function in regulating HSF1 transcriptional activity.

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“…Upon phosphorylation, HSF1 undergoes trimerization, translocates to the nucleus, and then activates Hspa1a transcription by binding to site-specific heat shock elements present in the Hspa1 promoter sequence [ 18 , 24 , 25 ]. It is noteworthy that HSF1 can be phosphorylated by multiple signaling pathways including PKA [ 18 , 26 , 27 ]. In the present study, we found that HG significantly inhibited PKA activity in HUVECs (Supplementary Figure 1 ), which is consistent with a previous finding obtained in human retinal endothelial cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein 70 Mediates the Protective Effect of Naringenin on High-Glucose-Induced Alterations of Endothelial Function

Zhang

Liu

et al. 2022

International Journal of Endocrinology

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Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vascular complications. Naringenin (Nar) is a flavanone bioactive isolated from citrus fruits known to have in vitro and in vivo antidiabetic properties. However, whether Nar affects endothelial function remains unclear in diabetes or under high-glucose (HG) condition. Using an in vitro model of hyperglycemia in human umbilical vein endothelial cells (HUVECs), we found that Nar administration markedly attenuated HG-induced alterations of endothelial function, evidenced by the mitigation of oxidative stress and inflammation, the reduction of cell adhesion molecular expressions, and the improvement of insulin resistance. We also found that HG exposure significantly reduced the levels of intracellular heat shock protein 70 (iHSP70 or iHSPA1A) and the release of HSP70 from HUVECs. HSP70 depletion mimicked and clearly diminished the protective effects of Nar on HG-induced alterations of endothelial function. In addition, Nar treatment significantly enhanced iHSP70 protein levels through a transcription-dependent manner. These results demonstrated that Nar could protect HUVECs against HG-induced alterations of endothelial function through upregulating iHSP70 protein levels. These findings are also helpful in providing new therapeutic strategies that are promising in the clinical use of Nar for the treatment of diabetes and diabetic complications.

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Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation

Cited by 13 publications

References 37 publications

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

Heat Shock Protein 70 Mediates the Protective Effect of Naringenin on High-Glucose-Induced Alterations of Endothelial Function

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