Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN.
Caspase 8 is a cysteine protease regulated in both a death-receptor-dependent and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methylation as well as through gene deletion. Complete inactivation of CASP8 occurred almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by programmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor in neuroblastomas with amplification of MYCN.
Teitz
T
T
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38101, USA.
Wei
T
T
Valentine
M B
MB
Vanin
E F
EF
Grenet
J
J
Valentine
V A
VA
Behm
F G
FG
Look
A T
AT
Lahti
J M
JM
Kidd
V J
VJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics*; D002648:Child; D019175:DNA Methylation; D004317:Doxorubicin / Q000494:pharmacology; D005784:Gene Amplification; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016259:Genes, myc; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D004317:Doxorubicin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases