Involvement of caspase-2 long isoform in Fas-mediated cell death of human leukemic cells

Abstract

IntroductionApoptosis can be induced in many cell types by engagement of the Fas (CD95/APO-1) receptor by its natural ligand (FasL) or agonistic antibodies (anti-Fas Ab). 1,2 Fas-mediated cell death was proposed to play a role in T-cell 3 and erythroid cell 4 homeostasis. Fas receptor was also suggested to be involved in the early phase of cytotoxic drugmediated leukemic cell apoptosis. 5,6 Signaling through Fas requires its aggregation and the formation of an intracellular protein complex referred to as the death-inducing signaling complex (DISC). 7,8 This complex consists of the cytoplasmic domain of Fas, the adaptor molecule FADD/MORT-1, and the cysteine aspartic acid-specific protease Mch5/Flice/Mach/procaspase-8. [9][10][11][12][13] This latter protein belongs to a family of structurally related cysteine proteases that currently includes 14 enzymes in mammals. 14 All are synthesized as inactive proenzymes that have to be cleaved at key aspartate residues to be activated. 15 Caspases can be divided into 2 groups according to the length of their prodomain, those with a short prodomain (procaspase-3, -6, and -7) and those with a long prodomain (the remainder). These enzymes were shown to function as a proteolytic cascade in which caspases with a long prodomain act upstream of those with a short prodomain. 16 In the Fasmediated cell death pathway, caspase-3 was suggested to play an important role in the cascade, downstream of caspase-8. 17 The binding of procaspase-8 to FADD/MORT-1 is mediated through tandem death effector domains (DED). The FLICEinhibitory protein, c-FLIP (Casper/I-Flice/Flame-1/Cash/Clarp/ Mrit/Usurpin) that contains similar DED but an inactive caspase domain, interferes with the formation of a functional DISC. [18][19][20][21][22][23][24][25] On recruitment to the DISC, procaspase-8 is processed into its active subunits, which are released from the complex to cleave intracellular substrates and to signal apoptosis. 26 The amount of active caspase-8 generated at the DISC and the level of expression of procaspase-3 could determine whether downstream pathways involve the mitochondria or not. 27 Type I cells in which caspase-8 directly activates downstream caspases to induce the cell demise were distinguished from type II cells in which caspases have to cleave the proapoptotic BH3 domainonly protein of the Bcl-2 family known as Bid to trigger cell death. 28,29 In this latter pathway, cleaved/activated Bid migrates from the cytosol to the mitochondria and induces the opening of the permeability transition pores, the loss of inner mitochondrial transmembrane potential, and the release of apoptogenic factors such as cytochrome c and apoptosis-inducing factor (AIF). [30][31][32][33] In the cytosol, cytochrome c triggers oligomerization of the adaptor molecule APAF-1 in the presence of adenosine triphosphate (ATP). Oligomerized APAF-1 recruits and activates caspase-9 For personal use only. on May 10, 2018. by guest www.bloodjournal.org From that, in turn, activates caspase-3 and other downstream casp...

Phellinus linteus activates different pathways to induce apoptosis in prostate cancer cells

“…From the analysis of its primary structure, caspase 2 contains a long NH 2 -terminal prodomain, which is used by apoptotic stimuli to initiate apoptosis, and an optimal recognition motif of downstream caspases to execute apoptotic processes (Harvey et al, 1997;Droin et al, 2001). To further search for the cause of the different sensitivities of LNCaP and PC3 cells to PL-induced apoptosis, the expression of caspase 2 was examined by immunoblotting ( Figure 3A).…”

“…Among caspase family members, caspase 2 is unique because it has features of both the long prodomain of upstream caspases and the optimal recognition motif of downstream caspases (Harvey et al, 1997;Droin et al, 2001). The prodomain is essential for the dimerisation and autoprocessing of precursor caspase 2, which allow caspase 2 to be directly activated and further initiate the caspase cascade in response to various apoptotic stimuli (Harvey et al, 1997;Droin et al, 2001).The endoplasmic reticulum (ER) is the main intracellular organelle in charge of proper folding and maturation of transmembrane and secretory proteins (Kaufman 1999;Patil and Walter, 2001;Demaurex and Distelhorst, 2003). Studies have demonstrated that the ER functions as a sensor of cellular stress to maintain homeostasis in cells Hendershot, 2001, 2004;Rutkowski and Kaufman, 2004;Schroder and Kaufman, 2005).…”

“…Among caspase family members, caspase 2 is unique because it has features of both the long prodomain of upstream caspases and the optimal recognition motif of downstream caspases (Harvey et al, 1997;Droin et al, 2001). The prodomain is essential for the dimerisation and autoprocessing of precursor caspase 2, which allow caspase 2 to be directly activated and further initiate the caspase cascade in response to various apoptotic stimuli (Harvey et al, 1997;Droin et al, 2001).…”

Developmental cell death during Xenopus metamorphosis involves BID cleavage and caspase 2 and 8 activation

“…Indeed, the activation of caspase-2 is shown to precede the processing of caspase-8 during ascididemin-induced apoptosis (Dirsch et al, 2004) or during ceramide-and etoposide-induced apoptosis (Lin et al, 2004). But in other cases, TNF␣-induced death and Fasmediated death data suggest that caspases-2 and -8 might be independently activated (Bergeron et al, 1998;Droin et al, 2001).…”

Nonsense-mediated mRNA decay among human caspases: the caspase-2S putative protein is encoded by an extremely short-lived mRNA

“…1 Several human genes encoding caspases can undergo alternative mRNA splicing, which may lead to the production of shorter proteins. 2 Caspase-2 can function as both an initiator 3 and an effector 4 caspase, depending on the death stimulus and the cell type. The 12 exon-containing CASP-2 gene has been originally described to encode two isoforms with opposite roles in apoptosis.…”