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Titolo:
A DEVD-INHIBITED CASPASE OTHER THAN CPP32 IS INVOLVED IN THE COMMITMENT OF CEREBELLAR GRANULE NEURONS TO APOPTOSIS INDUCED BY K+ DEPRIVATION
Autore:
DMELLO SR; AGLIECO F; ROBERTS MR; BORODEZT K; HAYCOCK JW;
Indirizzi:
UNIV CONNECTICUT,DEPT PHYSIOL & NEUROBIOL,U-156,3107 HORSEBARN HILL RD STORRS CT 06269 LOUISIANA STATE UNIV,MED CTR,DEPT BIOCHEM NEW ORLEANS LA 70112
Titolo Testata:
Journal of neurochemistry
fascicolo: 5, volume: 70, anno: 1998,
pagine: 1809 - 1818
SICI:
0022-3042(1998)70:5<1809:ADCOTC>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
DEATH GENE CED-3; CELL-DEATH; IL-1-BETA-CONVERTING ENZYME; MICE DEFICIENT; AMINO-ACIDS; PROTEASE; DEPOLARIZATION; POTASSIUM; DIFFERENTIATION; ACTIVATION;
Keywords:
YL-ASP-CENTER-DOT(O-METHYL)CENTER-DOT-FLUOROMETHYL KETONE; CPP32; NEDD2; NEURONAL SURVIVAL; POLY(ADP-RIBOSE) POLYMERASE; ZYLOXYCARBONYL-VAL-ALA-ASP-CENTER-DOT-FLUOROMETHYL KETONE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
54
Recensione:
Indirizzi per estratti:
Citazione:
S.R. Dmello et al., "A DEVD-INHIBITED CASPASE OTHER THAN CPP32 IS INVOLVED IN THE COMMITMENT OF CEREBELLAR GRANULE NEURONS TO APOPTOSIS INDUCED BY K+ DEPRIVATION", Journal of neurochemistry, 70(5), 1998, pp. 1809-1818

Abstract

Cultured cerebellar granule neurons undergo apoptosis when switched from a medium containing depolarizing levels of K+ (25 mM KCl) to medium containing lower levels of K+ (5 mM KCl). We used this paradigm to investigate the role of caspases in the death process. Two broad-spectrum caspase inhibitors, tert-butoxycarbonyl-Asp.(O-methyl).fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp.fluoromethyl ketone, significantly reduced cell death (90 and 60%, respectively) at relatively lowconcentrations (10-25 mu M), suggesting that caspase activation is involved in the apoptotic process. DNA fragmentation, a hallmark of apoptosis, was also reduced by these caspase inhibitors, suggesting that caspase activation occurred upstream of DNA cleavage in the sequence ofevents leading to cell death. As a step toward identifying the caspase(s) involved, the effects of N-acetyl Tyr-Val-Ala-Asp.chloromethyl ketone (YVAD.cmk), an interleukin-1 beta converting enzyme-preferring inhibitor, and N-acetyl Asp-Glu-Val-Asp.fluoromethyl ketone (DEVD.fmk), a CPP32-preferring inhibitor, were also evaluated. YVAD.cmk provided only modest (<20%) protection and only at the highest concentration (100 mu M) tested, suggesting that interleukin-lp converting enzyme and/or closely related caspases were not involved. In comparison, DEVD.fmk inhibited cell death by up to 50%. Western blot analyses, however, failed to detect an increase in processing/activation of CPP32 or in the proteolysis of a CPP32 substrate, poly(ADP-ribose) polymerase, during the induction of apoptosis in granule neurons. Similarly, the levels of Nedd2, a caspase that is highly expressed in the brain and that is partially inhibited by DEVD.fmk, also remained unaffected in apoptotic neurons undergoing apoptosis. These results suggest that a DEVD-sensitive caspase other than CPP32 or Nedd2 mediates the induction of apoptosis in K+-deprived granule neurons.

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Documento generato il 01/12/20 alle ore 13:36:49