PMID- 15326478
OWN - NLM
STAT- MEDLINE
DCOM- 20041102
LR  - 20061115
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 23
IP  - 45
DP  - 2004 Sep 30
TI  - A novel isoform of pro-interleukin-18 expressed in ovarian tumors is resistant to 
      caspase-1 and -4 processing.
PG  - 7552-60
AB  - Interleukin-18 (IL-18) is a proinflammatory cytokine synthesized as a 24 kDa 
      inactive precursor (pro-IL-18) by several cell types, and is processed to a 
      bioactive molecule of 18 kDa by the proteinases caspase-1 or caspase-4. All 
      ovarian carcinoma cell lines express pro-IL-18, only in some instances coexpress 
      caspase-1, and always express caspase-4; in any case, they display a defective 
      processing of IL-18. We analysed whether pro-IL-18, present in two ovarian 
      carcinoma cell lysates, could be processed 'in vitro' by recombinant active 
      caspase-1. While most of pro-IL-18 could be cleaved by caspase-1, a residual of 
      pro-IL-18 appeared to be resistant. Cloning and sequence analysis of the whole 
      pro-IL-18 open reading frame demonstrated the existence of an alternatively 
      spliced mRNA variant, which lacked exon-3 (Delta3pro-IL-18). The 12 bp exon-3 
      encodes for the AEDD amino-acid sequence, which is N-terminal with respect to the 
      cleavage site of caspase-1. Both pro-IL-18 and Delta3pro-IL-18 mRNA isoforms were 
      detected in all ovarian cancer cell lines analysed, while Delta3pro-IL-18 mRNA 
      was undetectable in normal ovarian epithelial cells. The Delta3pro-IL-18 cDNA 
      induced synthesis of an alternative Delta3pro-IL-18 protein upon transfection 
      into a murine cell line. The Delta3pro-IL-18 protein was resistant to proteolytic 
      activation by caspase-1 and -4, although it was capable to bind caspase-1. 
      Aternative splicing of pro-IL-18 exon-3 may represent a novel mechanism of 
      regulation of bioactive IL-18 production in human ovarian tumors.
FAU - Gaggero, Alessia
AU  - Gaggero A
AD  - Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 
      Genoa, Italy.
FAU - De Ambrosis, Alessandro
AU  - De Ambrosis A
FAU - Mezzanzanica, Delia
AU  - Mezzanzanica D
FAU - Piazza, Tiziana
AU  - Piazza T
FAU - Rubartelli, Anna
AU  - Rubartelli A
FAU - Figini, Mariangela
AU  - Figini M
FAU - Canevari, Silvana
AU  - Canevari S
FAU - Ferrini, Silvano
AU  - Ferrini S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (DNA Primers)
RN  - 0 (Interleukin-18)
RN  - 0 (Protein Precursors)
RN  - 0 (Recombinant Proteins)
RN  - EC 3.4.22.- (CASP4 protein, human)
RN  - EC 3.4.22.- (Caspases)
RN  - EC 3.4.22.- (Caspases, Initiator)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Base Sequence
MH  - Blotting, Southern
MH  - Blotting, Western
MH  - Caspase 1/*metabolism
MH  - Caspases/*metabolism
MH  - Caspases, Initiator
MH  - Cell Line, Tumor
MH  - DNA Primers
MH  - Female
MH  - Humans
MH  - Interleukin-18/*metabolism
MH  - Ovarian Neoplasms/enzymology/*metabolism/pathology
MH  - Protein Precursors/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2004/08/25 05:00
MHDA- 2004/11/04 09:00
CRDT- 2004/08/25 05:00
PHST- 2004/08/25 05:00 [pubmed]
PHST- 2004/11/04 09:00 [medline]
PHST- 2004/08/25 05:00 [entrez]
AID - 1208036 [pii]
AID - 10.1038/sj.onc.1208036 [doi]
PST - ppublish
SO  - Oncogene. 2004 Sep 30;23(45):7552-60. doi: 10.1038/sj.onc.1208036.