Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis

Ferrari, D.Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany (författare)

Apoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug-induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
NATURVETENSKAP Biologi Cellbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Cell Biology hsv//eng
anticancer drugs
apo-1/fas receptor/ligand system
Apoptosis
atp
Bcl-2
CD95 (APO-1/Fas)
cell-death
crma-inhibitable protease
cytochrome c
cytochrome-c
fas-mediated apoptosis
flice
Mitochondria
signaling complex disc
wild-type

Stepczynska, A.Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany (författare)
Los, Marek JanDepartment of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany(Swepub:liu)Marlo14 (författare)
Wesselborg, SebastianDepartment of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany (författare)
Schulze-Osthoff, KlausDepartment of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany (författare)
Department of Internal Medicine I, Eberhard-Karls University, D-72076 Tübingen, Germany (creator_code:org_t)

Ingår i:Journal of Experimental Medicine: Rockefeller University Press188:5, s. 979-9840022-10071540-9538

Av författaren/redakt...: Ferrari, D.; Stepczynska, A.; Los, Marek Jan; Wesselborg, Seba ...; Schulze-Osthoff, ...

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