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Heat shock proteins: essential proteins for apoptosis regulation.

Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C - J. Cell. Mol. Med. (2008)

Bottom Line: Several of these proteins have demonstrated to directly interact with components of the cell signalling pathways, for example those of the tightly regulated caspase-dependent programmed cell death machinery, upstream, downstream and at the mitochondrial level.HSPs can also affect caspase-independent apoptosis-like process by interacting with apoptogenic factors such as apoptosis-inducing factor (AIF) or by acting at the lysosome level.Our purpose will be illustrated by emerging strategies in targeting these protective proteins to treat haematological malignancies.

View Article: PubMed Central - PubMed

Affiliation: Inserm, UMR866, Dijon, France.

ABSTRACT
Many different external and intrinsic apoptotic stimuli induce the accumulation in the cells of a set of proteins known as stress or heat shock proteins (HSPs). HSPs are conserved proteins present in both prokaryotes and eukaryotes. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and stress-accumulated misfolded proteins, and by preventing their aggregation. HSPs have a protective function, that is they allow the cells to survive to otherwise lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several of these proteins have demonstrated to directly interact with components of the cell signalling pathways, for example those of the tightly regulated caspase-dependent programmed cell death machinery, upstream, downstream and at the mitochondrial level. HSPs can also affect caspase-independent apoptosis-like process by interacting with apoptogenic factors such as apoptosis-inducing factor (AIF) or by acting at the lysosome level. This review will describe the different key apoptotic proteins interacting with HSPs and the consequences of these interactions in cell survival, proliferation and apoptotic processes. Our purpose will be illustrated by emerging strategies in targeting these protective proteins to treat haematological malignancies.

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Schematic representation of HSPs regulatory function in the intrinsic (A), extrinsic and caspase independent pathways to death (B). (A) HSPs can block the mitochondrial intrinsic pathway of apoptosis by interacting with key proteins at three levels: (i) upstream the mitochondria, thereby modulating signalling pathways (HSP70 modulates the activation of stress-activated kinases such as Akt, JNK or ERK); (ii) at the mitochondrial level, controlling the release of cytochrome c (HSP27 by its interaction with the actin, HSP70 or HSP60 with Bax, and HSP90 with Bcl2) and (iii) at the post-mitochondrial level, by blocking apoptosis by their interaction with cytochrome c (HSP27), Apaf-1 (HSP70 or HSP90) or caspase-3 (HSP27). (B) At the death receptors level, HSP70 and HSP90 can interact with RIP favoring cell survival. HSP70 (through TRAIL and FADD recruitment) and HSP90 (through FLIP) block caspase 8 activation. HSP90 and HSP70 inhibit Bid cleavage while HSP27 affects Bid mitochondrial re-distribution. At the caspase-independent pathways level, HSP70 neutralizes AIF and inhibits cathepsines release from lysosomes. AKS1 pathway is affected directly by HSP70 or through Daxx by HSP27. Inhibition: −/, activation: →.
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fig01: Schematic representation of HSPs regulatory function in the intrinsic (A), extrinsic and caspase independent pathways to death (B). (A) HSPs can block the mitochondrial intrinsic pathway of apoptosis by interacting with key proteins at three levels: (i) upstream the mitochondria, thereby modulating signalling pathways (HSP70 modulates the activation of stress-activated kinases such as Akt, JNK or ERK); (ii) at the mitochondrial level, controlling the release of cytochrome c (HSP27 by its interaction with the actin, HSP70 or HSP60 with Bax, and HSP90 with Bcl2) and (iii) at the post-mitochondrial level, by blocking apoptosis by their interaction with cytochrome c (HSP27), Apaf-1 (HSP70 or HSP90) or caspase-3 (HSP27). (B) At the death receptors level, HSP70 and HSP90 can interact with RIP favoring cell survival. HSP70 (through TRAIL and FADD recruitment) and HSP90 (through FLIP) block caspase 8 activation. HSP90 and HSP70 inhibit Bid cleavage while HSP27 affects Bid mitochondrial re-distribution. At the caspase-independent pathways level, HSP70 neutralizes AIF and inhibits cathepsines release from lysosomes. AKS1 pathway is affected directly by HSP70 or through Daxx by HSP27. Inhibition: −/, activation: →.

Mentions: Growth factors, such as nerve growth factor or platelet-derived growth factor, induce cell survival by activating the phosphatidylinositol 3-kinase pathway (PI3-K). Activated PI3-K phosphorylates inositol lipids in the plasma membrane that attract the serine/threonine kinase Akt/PKB, a protein that generates a survival signal in response to growth factor stimulation. Akt targets multiple proteins of the apoptotic machinery [34, 35], including Bad [36] and caspase-9 [37]. HSP27 has been described to have prosurvival effects through its interaction with the protein kinase Akt, an association that is necessary for Akt activation in stressed cells (Fig. 1A). In turn, Akt can phosphorylate HSP27, thus leading to the disruption of HSP27-Akt complexes [38]. HSP27 can also bind to F-actin and prevent the disruption of the cytoskeleton resulting either from heat shock, cytochalasin D or from other stresses. This has been reported to affect mitochondria membrane structure and thereby the release of mitochondrial apoptogenic molecules such as cytochrome c [39]. Recently, we have demonstrated that HSP27 protection to apoptosis induced by etoposide or TNF-α in different cancer cell lines can result from an increase in the activity of the survival transcription factor nuclear factor-κB (NF-κB). NF-κB is involved in the expression of several anti-apoptotic proteins, such as Bcl-2, Bcl-xL and c-IAPs. HSP27 effect on NF-κB results from an increase in the ubiquitination and proteasomal degradation of the NF-κB inhibitor I-κBα[40] (Fig. 1B). HSP27 also increases the ubiquitination and proteasomal degradation of the cell cycle protein p27kip1 under stress conditions. As a consequence, cell proliferation, once the stress conditions are over, is facilitated [41] (Fig. 1B).


Heat shock proteins: essential proteins for apoptosis regulation.

Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C - J. Cell. Mol. Med. (2008)

Schematic representation of HSPs regulatory function in the intrinsic (A), extrinsic and caspase independent pathways to death (B). (A) HSPs can block the mitochondrial intrinsic pathway of apoptosis by interacting with key proteins at three levels: (i) upstream the mitochondria, thereby modulating signalling pathways (HSP70 modulates the activation of stress-activated kinases such as Akt, JNK or ERK); (ii) at the mitochondrial level, controlling the release of cytochrome c (HSP27 by its interaction with the actin, HSP70 or HSP60 with Bax, and HSP90 with Bcl2) and (iii) at the post-mitochondrial level, by blocking apoptosis by their interaction with cytochrome c (HSP27), Apaf-1 (HSP70 or HSP90) or caspase-3 (HSP27). (B) At the death receptors level, HSP70 and HSP90 can interact with RIP favoring cell survival. HSP70 (through TRAIL and FADD recruitment) and HSP90 (through FLIP) block caspase 8 activation. HSP90 and HSP70 inhibit Bid cleavage while HSP27 affects Bid mitochondrial re-distribution. At the caspase-independent pathways level, HSP70 neutralizes AIF and inhibits cathepsines release from lysosomes. AKS1 pathway is affected directly by HSP70 or through Daxx by HSP27. Inhibition: −/, activation: →.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401125&req=5

fig01: Schematic representation of HSPs regulatory function in the intrinsic (A), extrinsic and caspase independent pathways to death (B). (A) HSPs can block the mitochondrial intrinsic pathway of apoptosis by interacting with key proteins at three levels: (i) upstream the mitochondria, thereby modulating signalling pathways (HSP70 modulates the activation of stress-activated kinases such as Akt, JNK or ERK); (ii) at the mitochondrial level, controlling the release of cytochrome c (HSP27 by its interaction with the actin, HSP70 or HSP60 with Bax, and HSP90 with Bcl2) and (iii) at the post-mitochondrial level, by blocking apoptosis by their interaction with cytochrome c (HSP27), Apaf-1 (HSP70 or HSP90) or caspase-3 (HSP27). (B) At the death receptors level, HSP70 and HSP90 can interact with RIP favoring cell survival. HSP70 (through TRAIL and FADD recruitment) and HSP90 (through FLIP) block caspase 8 activation. HSP90 and HSP70 inhibit Bid cleavage while HSP27 affects Bid mitochondrial re-distribution. At the caspase-independent pathways level, HSP70 neutralizes AIF and inhibits cathepsines release from lysosomes. AKS1 pathway is affected directly by HSP70 or through Daxx by HSP27. Inhibition: −/, activation: →.
Mentions: Growth factors, such as nerve growth factor or platelet-derived growth factor, induce cell survival by activating the phosphatidylinositol 3-kinase pathway (PI3-K). Activated PI3-K phosphorylates inositol lipids in the plasma membrane that attract the serine/threonine kinase Akt/PKB, a protein that generates a survival signal in response to growth factor stimulation. Akt targets multiple proteins of the apoptotic machinery [34, 35], including Bad [36] and caspase-9 [37]. HSP27 has been described to have prosurvival effects through its interaction with the protein kinase Akt, an association that is necessary for Akt activation in stressed cells (Fig. 1A). In turn, Akt can phosphorylate HSP27, thus leading to the disruption of HSP27-Akt complexes [38]. HSP27 can also bind to F-actin and prevent the disruption of the cytoskeleton resulting either from heat shock, cytochalasin D or from other stresses. This has been reported to affect mitochondria membrane structure and thereby the release of mitochondrial apoptogenic molecules such as cytochrome c [39]. Recently, we have demonstrated that HSP27 protection to apoptosis induced by etoposide or TNF-α in different cancer cell lines can result from an increase in the activity of the survival transcription factor nuclear factor-κB (NF-κB). NF-κB is involved in the expression of several anti-apoptotic proteins, such as Bcl-2, Bcl-xL and c-IAPs. HSP27 effect on NF-κB results from an increase in the ubiquitination and proteasomal degradation of the NF-κB inhibitor I-κBα[40] (Fig. 1B). HSP27 also increases the ubiquitination and proteasomal degradation of the cell cycle protein p27kip1 under stress conditions. As a consequence, cell proliferation, once the stress conditions are over, is facilitated [41] (Fig. 1B).

Bottom Line: Several of these proteins have demonstrated to directly interact with components of the cell signalling pathways, for example those of the tightly regulated caspase-dependent programmed cell death machinery, upstream, downstream and at the mitochondrial level.HSPs can also affect caspase-independent apoptosis-like process by interacting with apoptogenic factors such as apoptosis-inducing factor (AIF) or by acting at the lysosome level.Our purpose will be illustrated by emerging strategies in targeting these protective proteins to treat haematological malignancies.

View Article: PubMed Central - PubMed

Affiliation: Inserm, UMR866, Dijon, France.

ABSTRACT
Many different external and intrinsic apoptotic stimuli induce the accumulation in the cells of a set of proteins known as stress or heat shock proteins (HSPs). HSPs are conserved proteins present in both prokaryotes and eukaryotes. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and stress-accumulated misfolded proteins, and by preventing their aggregation. HSPs have a protective function, that is they allow the cells to survive to otherwise lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several of these proteins have demonstrated to directly interact with components of the cell signalling pathways, for example those of the tightly regulated caspase-dependent programmed cell death machinery, upstream, downstream and at the mitochondrial level. HSPs can also affect caspase-independent apoptosis-like process by interacting with apoptogenic factors such as apoptosis-inducing factor (AIF) or by acting at the lysosome level. This review will describe the different key apoptotic proteins interacting with HSPs and the consequences of these interactions in cell survival, proliferation and apoptotic processes. Our purpose will be illustrated by emerging strategies in targeting these protective proteins to treat haematological malignancies.

Show MeSH
Related in: MedlinePlus