Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3

Abstract

The release of mitochondrial cytochrome c by genotoxic stress induces the formation of a cytosolic complex with Apaf-1 (mammalian CED4 homolog) and thereby the activation of procaspase-3 (cas-3) and procaspase-9 (cas-9). Here we demonstrate that heat-shock protein 27 (Hsp27) inhibits cytochrome c (cyt c)-dependent activation of cas-3. Hsp27 had no e ect on cyt c release, Apaf-1 and cas-9 activation. By contrast, our results show that Hsp27 associates with cas-3, but not Apaf-1 or cas-9, and inhibits activation of cas-3 by cas-9-mediated proteolysis. Furthermore, the present results demonstrate that immunodepletion of Hsp27 depletes cas-3. Importantly, treatment of cells with DNA damaging agents dissociates the Hsp27/cas-3 complex and relieves inhibition of cas-3 activation. These ®ndings de®ne a novel function for Hsp27 and provide the ®rst evidence that a heat shock protein represses cas-3 activation.

Human αA- and αB-crystallins bind to Bax and Bcl-XS to sequester their translocation during staurosporine-induced apoptosis

“…However, the exact mechanism or regulating targets seem to be different. Hsp27 prevents apoptosis by interacting with caspase-3 to modulate its activity, [47][48] by interacting with cytochrome c to prevent procaspase-9 activation, 49 or by regulating Bid intracellular distribution and F actin integrity to block mitochondrial death pathway. 52 In contrast, a-crystallin utilizes a different mechanism to negatively regulate caspase-3 activity.…”

“…Its proapoptotic ability can be inhibited by Bcl-2 and Bcl-X L . 38 Another important group of apoptosis regulators are heatshock proteins that include alpha-crystallins (a-crystallins), [39][40][41][42][43][44][45][46] Hsp27, [39][40][47][48][49][50][51][52] Hsp70, [53][54][55][56][57] Hsp90 58 and Hsp60. [59][60] While Hsp60 appears to enhance apoptosis by promoting maturation of procaspase-3, 59,60 the majority of these factors seems to protect cells from induced apoptosis through different mechanisms.…”

“…47,48 It also binds to caspase-3 and modulates the activity of caspase-3. 49 Finally, Hsp27 can abrogate apoptotic pathway through regulation of Bid intracellular distribution and protection of F-actin integrity. 52 Both a-crystallins and Hsp27 are closely related family members.…”

Viability of unstimulated lymphocytes exposed to extremely low frequency electromagnetic fields is dependent on intensity

“…Phosphorylated HSP27 has been shown to inhibit apoptosis by forming complex with apoptosome (complex of Apaf-1 protein, pro-caspase 9 and cytochrome C), or some of its components, and preventing proteolytic activation of pro-caspase 9 into active form of caspase 9. This in turn prevents activation of pro-caspase 3 which is activated by caspase 9, leading to the inhibition of apoptosis [45,46].Apoptosis is a highly regulated form of cell death. It is a fundamental physiological process crucial to maintaining homeostasis in multicellular organisms acting as a counterbalance to cell division.…”

Big wheel keeps on turning: apoptosome regulation and its role in chemoresistance

“…Some of the key regulators, including the oncoprotein ProT and the tumor suppressor protein PHAP, and their principal points of interaction with the major steps of apoptosome formation and activation, are depicted in this schematic figure. See the text for a discussion of the positive and negative modulation of apoptosome function by these factors activation of procaspase-9 (reference Pandey et al 69 ). Hsp27 inhibits cytochrome c-mediated caspase activation through a mechanism that involves binding to and sequestering of cytochrome c, preventing its interaction with Apaf-1 (references Bruey et al 70 and Pandey et al 71 ). Moreover, Hsp27 has been found to prevent Smac release from mitochondria in multiple myeloma cell lines and patient-derived cells, which could help to explain the resistance of these cancer cells to certain apoptotic stimuli.…”