PMID- 18257744
OWN - NLM
STAT- MEDLINE
DCOM- 20080716
LR  - 20211020
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 412
IP  - 3
DP  - 2008 Jun 15
TI  - Calmodulin binding to cellular FLICE-like inhibitory protein modulates 
      Fas-induced signalling.
PG  - 459-68
LID - 10.1042/BJ20071507 [doi]
AB  - We and others have demonstrated that Fas-mediated apoptosis is a potential 
      therapeutic target for cholangiocarcinoma. Previously, we reported that CaM 
      (calmodulin) antagonists induced apoptosis in cholangiocarcinoma cells through 
      Fas-related mechanisms. Further, we identified a direct interaction between CaM 
      and Fas with recruitment of CaM into the Fas-mediated DISC (death-inducing 
      signalling complex), suggesting a novel role for CaM in Fas signalling. Therefore 
      we characterized the interaction of CaM with proteins recruited into the 
      Fas-mediated DISC, including FADD (Fas-associated death domain)-containing 
      protein, caspase 8 and c-FLIP cellular FLICE [FADD (Fas-associated death 
      domain)-like interleukin 1beta-converting enzyme]-like inhibitory protein. A 
      Ca(2+)-dependent direct interaction between CaM and FLIP(L), but not FADD or 
      caspase 8, was demonstrated. Furthermore, a 37.3+/-5.7% increase (n=6, P=0.001) 
      in CaM-FLIP binding was observed at 30 min after Fas stimulation, which returned 
      to the baseline after 60 min and correlated with a Fas-induced increase in 
      intracellular Ca(2+) that reached a peak at 30 min and decreased gradually over 
      60 min in cholangiocarcinoma cells. A CaM antagonist, TFP (trifluoperazine), 
      inhibited the Fas-induced increase in CaM-FLIP binding concurrent with inhibition 
      of ERK (extracellular-signal-regulated kinase) phosphorylation, a downstream 
      signal of FLIP. Direct binding between CaM and FLIP(L) was demonstrated using 
      recombinant proteins, and a CaM-binding region was identified in amino acids 
      197-213 of FLIP(L). Compared with overexpression of wild-type FLIP(L) that 
      resulted in decreased spontaneous as well as Fas-induced apoptosis, mutant 
      FLIP(L) with deletion of the CaM-binding region resulted in increased spontaneous 
      and Fas-induced apoptosis in cholangiocarcinoma cells. Understanding the biology 
      of CaM-FLIP binding may provide new therapeutic targets for cholangiocarcinoma 
      and possibly other cancers.
FAU - Pawar, Pritish S
AU  - Pawar PS
AD  - Department of Pathology, University of Alabama at Birmingham, LHRB 533, 1530 3rd 
      Ave South, Birmingham, AL 35294, USA.
FAU - Micoli, Keith J
AU  - Micoli KJ
FAU - Ding, Haitao
AU  - Ding H
FAU - Cook, William J
AU  - Cook WJ
FAU - Kappes, John C
AU  - Kappes JC
FAU - Chen, Yabing
AU  - Chen Y
FAU - McDonald, Jay M
AU  - McDonald JM
LA  - eng
GR  - R01 CA109119/CA/NCI NIH HHS/United States
GR  - R24DK64400/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (Calmodulin)
RN  - 0 (FAS protein, human)
RN  - 0 (fas Receptor)
RN  - EC 3.4.22.- (CASP8 protein, human)
RN  - EC 3.4.22.- (Caspase 8)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Apoptosis
MH  - Binding Sites
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein/*metabolism
MH  - Calcium/metabolism
MH  - Calmodulin/*metabolism
MH  - Caspase 8/metabolism
MH  - Cell Line, Tumor
MH  - Humans
MH  - *Signal Transduction
MH  - fas Receptor/*metabolism
EDAT- 2008/02/09 09:00
MHDA- 2008/07/17 09:00
CRDT- 2008/02/09 09:00
PHST- 2008/02/09 09:00 [pubmed]
PHST- 2008/07/17 09:00 [medline]
PHST- 2008/02/09 09:00 [entrez]
AID - BJ20071507 [pii]
AID - 10.1042/BJ20071507 [doi]
PST - ppublish
SO  - Biochem J. 2008 Jun 15;412(3):459-68. doi: 10.1042/BJ20071507.