Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo

Hakem, Razqallah; Hakem, Anne; Duncan, Gordon S.; Henderson, Jeffrey T.; Woo, Minna; Soengas, Marı́a S.; Elia, Andrew; Pompa, José Luis de la; Kägi, David; Khoo, Wilson; Potter, Julia M.; Yoshida, Ritsuko; Kaufman, Stephen A.; Lowe, Scott W.; Penninger, Josef; Mak, Tak W.

doi:10.1016/s0092-8674(00)81477-4

Cited by 1,187 publications

(826 citation statements)

References 42 publications

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“…Several lines of evidence support the idea that caspase-9 is the essential caspase in many forms of apoptosis (Li et al, 1997b;Kuida et al, 1998;Hakem et al, 1998;Sun et al, 1999). In addition, although caspase-8 has been initially suggested to interact with Apaf-1, a more detailed analysis showed that caspase-9 is the only Apaf-1 interacting protease in living cells (Slee et al, 1999).…”

Section: Discussionmentioning

confidence: 88%

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

et al. 2000

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Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either de®cient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-x L prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less e ective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.

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Section: Discussionmentioning

confidence: 88%

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

et al. 2000

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“…Because procaspase 9, procaspase 3, and PARP are associated with the apoptotic cell death pathway [37], we next examined their levels in guggulsterone-treated U937 cells.…”

Section: Guggulsterone Induces Cleavage Of Procaspase 9 Procaspase 3mentioning

confidence: 99%

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

Shishodia

Sethi

Ahn

et al. 2007

Biochemical Pharmacology

129

119

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Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and, p27. Guggulsterone induced apoptosis as indicated by increase in the number of Annexin V-and TUNEL-positive cells, through the down-regulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase 8, bid cleavage, cytochrome c release, caspase 9 activation, caspase 3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and down-regulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and down-regulation of anti-apoptotic protein expression.

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“…The defect in the execution of apoptotic cell death was caused by the failure to initiate JNK-induced cytochrome c release from the mitochondria [204]. This malfunction is significant since it is critical for the subsequent sequential activation of Apaf-1 [120], the initiator-caspase caspase-9 [76] and finally the effector-caspase caspase-3 [217] all of which are essential in the execution of apoptosis. Tournier et al [204] suggested that the apoptotic response is suppressed in JNK null MEF due to the absence of JNK, which is needed to initiate the apoptotic cascade (Fig.…”

Section: Map Kinase Signalingmentioning

confidence: 99%

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

Schroeter

Boyd

Spencer

et al. 2002

Neurobiology of Aging

310

178

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Oxidative and nitrosative stress is increasingly associated with the pathology of neurodegeneration and aging. The molecular mechanisms underlying oxidative/nitrosative stress-induced neuronal damage are emerging and appear to involve a mode of death in which mitogen-activated protein kinase (MAPK) signaling pathways are strongly implicated. Thus, attention is turning towards the modulation of intracellular signaling as a therapeutic approach against neurodegeneration. Both endogenous and dietary agents have been suggested as potent modulators of intracellular signal transduction, e.g. nitric oxide and flavonoids, respectively. This review addresses recent findings on the biological effects of flavonoids and nitric oxide in neurodegeneration and aims to elucidate the rationale for their prospective use as modulators of cellular signal transduction. © 2002 Elsevier Science Inc. All rights reserved.Keywords: Apoptosis; Oxidative stress; Neuron; Flavonoids; MAP kinase; JNK; ERK; Epicatechin; Nitric oxide; Mitochondria; Redox status; Polyphenols Abbreviations: AKT, serine/threonine kinase (also known as protein kinase B); AP-1, activator protein-1; Apaf-1, apoptosis protease activating factor-1; ASK1, apoptosis signal-regulating kinase-1; Bad, Bcl-2/BclX Lassociated death promoting protein; Bax, pro-apoptotic protein of the Bcl-2 family; Bcl-2, B-cell lymphoma 2: protein with anti-apoptotic properties; BclX L , long form of Bclx: anti-apoptotic protein of the Bcl-2 family; Caspase, cysteinyl aspartic acid-protease; c-Jun, mammalian equivalent of Jun: part of the AP-1 transcription complex; CREB, cAMP response element binding protein; DIABLO/smac, mitochondria-related pro-apoptotic protein: inhibits XIAP; ERK1/2, extracellular signal-related kinase; Fas, CD95: member of the TNF receptor family; GSHST, glutathione Stransferase; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEK1/2, ERK1/2-specific MAPKK; MKK4/7, JNK-specific MAPKK; MSK1, mitogen-and stress-activated kinase-1; NF-B, nuclear factor of immunoglobulin k locus in B-cells; ONOO − , peroxynitrite anion; p53, pro-apoptotic tumor suppressor gene product; PI3-kinase, phosphoinositol 3-kinase; Ras, small G-protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSK, pp90 ribosomal S6 kinase; SAPK, stressactivated protein kinase; XIAP, X-linked inhibitor of apoptosis: inhibits the activation of caspase-9

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Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo

Cited by 1,187 publications

References 42 publications

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

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