Heat shock proteins: essential proteins for apoptosis regulation

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 caspasedependent 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.

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

“…37 Given the known biological properties of the identified proteins, differential expression of 11 of them might explain the effects of DN-STAT5A and HSP might represent one major link between DN-STAT5A and apoptosis. Various studies have highlighted the protective effects of HSP against apoptosis in response to various stimuli such as hyperthermia, oxidative stress or staurosporine 38 From this point of view, the decreased expression of Hsp27 and Hsp70 might provide some cues to explain the susceptibility of NALM6D5A cells to apoptosis. We believe that the Hsp27 effect is mediated by Daxx, a protein involved in Fas-mediated cell death 31 given the increased proportion of Daxx in the cell cytoplasm together with the downregulation of Hsp27 expression and phosphorylation.…”

The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid

“…Moreover, it has been reported that the ATPase domain of HSP72 plays a key role in sequestering AIF in the cytosol, thereby inhibiting AIF nuclear translocation [38]. A potential additional mechanism that may contribute to increase the apoptosis resistance in TFK-1 cells is represented by the constitutive expression of pro-survival HSP27 [21,39,40]. This protein antagonizes BAX-mediated mitochondrial injury by inhibiting conformational activation of BAX thus reducing cytochrome c and AIF leakage and increasing significantly cell survival [37,41].…”

“…Among those proteins directly or indirectly linked to the BCL-2 protein family, the heat shock proteins (HSPs) play key roles in inhibiting the cell death pathway at multiple checkpoints [21].…”

“…Interestingly HSPs, and in particular HSP72, can affect the caspase-independent death pathway [22], interacting with apoptogenic proteins such as the apoptosis-inducing factor (AIF) [23] or by acting at lysosome level [21].…”

Instructive reconstruction: A new role for apoptosis in pattern formation

“…Our recently published research [3] has revealed an unexpected role for an antiapoptotic heat shock protein (HSP) [4], Hsc71, in Cnidarian pattern formation. While our research also has implications for stem cell and cancer biology, this article focuses on the patterning aspect of our findings, which could have broader implications for human congenital defects (see original publication).…”