2012
DOI: 10.1002/jcb.24155
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Type 1 inositol‐1,4,5‐trisphosphate receptor is a late substrate of caspases during apoptosis

Abstract: Apoptosis is characterized by the proteolytic cleavage of hundreds of proteins. One of them, the type 1 inositol-1,4,5-trisphosphate receptor (IP(3) R-1), a multimeric receptor located on the endoplasmic reticulum (ER) membrane that is critical to calcium homeostasis, was reported to be cleaved during staurosporine (STS) induced-apoptosis in Jurkat cells. Because the reported cleavage site separates the IP(3) binding site from the channel moiety, its cleavage would shut down a critical signaling pathway that i… Show more

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Cited by 16 publications
(11 citation statements)
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“…Furthermore, production of the 95 kDa C-terminal fragment was not evident in these experiments (open arrowhead, Fig. 2D), which is consistent with a recently published report [26]. The slow kinetics of IP 3 R-1 degradation in vitro and in intact cells would make it unlikely that caspase 3-mediated truncation of IP 3 R-1 contributes to the rapid mobilization of intracellular calcium seen with staurosporine treatment [14].…”
Section: Resultssupporting
confidence: 91%
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“…Furthermore, production of the 95 kDa C-terminal fragment was not evident in these experiments (open arrowhead, Fig. 2D), which is consistent with a recently published report [26]. The slow kinetics of IP 3 R-1 degradation in vitro and in intact cells would make it unlikely that caspase 3-mediated truncation of IP 3 R-1 contributes to the rapid mobilization of intracellular calcium seen with staurosporine treatment [14].…”
Section: Resultssupporting
confidence: 91%
“…Our results complement a study which was published while this paper was under review demonstrating that the IP 3 R-1 in not cleaved using several apoptotic paradigms, and that it is a poor substrate for caspase 3 in vitro [26]. We confirm and extend these findings in this study to show that caspase 3 does not contribute to apoptotic calcium release.…”
Section: Discussionsupporting
confidence: 90%
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“…For example, IP 3 R1 was shown to undergo caspase 3-dependent cleavage in various cell types, and this cleavage led to the formation of a C-terminal constitutively leaky channel termed a "channel-only domain" that mediates Ca 2ϩ release essential for complete execution of the apoptotic program (22,24,27). In contrast, it has been reported that IP 3 R1 is not cleaved in HEK293, HeLa, and Jurkat cells undergoing apoptosis in response to exposure to staurosporine, TNF␣, Trail, or UV irradiation (43). Moreover, these latter studies concluded that IP 3 R1 was, if at all, a very late caspase substrate during apoptosis.…”
Section: Discussionmentioning
confidence: 99%
“…It seems entirely plausible that this could result from steric hindrance by Bok of the ability of chymotrypsin and caspase-3 to access their cleavage sites. This inhibitory effect of Bok may well be biologically relevant, as the C-terminal IP 3 R1 fragment resulting from caspase-3 cleavage has been proposed to form an IP 3 -insensitive, "leaky" channel that contributes toward the apoptotic cascade (40,43), although this notion is controversial (44,50,51). Indeed, a very recent study shows that the IP 3 R1 fragments generated by caspase-3 remain associated and form functional channels fully capable of responding to IP 3 and contributing toward apoptosis (44).…”
Section: Discussionmentioning
confidence: 99%