PMID- 15265700
OWN - NLM
STAT- MEDLINE
DCOM- 20041004
LR  - 20231213
IS  - 0014-4827 (Print)
IS  - 0014-4827 (Linking)
VI  - 298
IP  - 2
DP  - 2004 Aug 15
TI  - Nuclear shuttling and TRAF2-mediated retention in the cytoplasm regulate the 
      subcellular localization of cIAP1 and cIAP2.
PG  - 535-48
AB  - Dynamic subcellular localization is an important regulatory mechanism for many 
      proteins. cIAP1 and cIAP2 are two closely related members of inhibitor of 
      apoptosis (IAP) family that play a role both as caspase inhibitors and as 
      mediators of tumor necrosis factor (TNF) receptor signaling. Here, we report that 
      cIAP1 and cIAP2 are nuclear shuttling proteins, whose subcellular localization is 
      mediated by the CRM1-dependent nuclear export pathway. Blocking export with 
      leptomycin B induces accumulation of both endogenous cIAP1 and epitope-tagged 
      cIAP1 and cIAP2 in the nucleus of human cancer cells. We have identified a new 
      CRM1-dependent leucine-rich nuclear export signal (NES) in the linker region 
      between cIAP1 BIR2 and BIR3 repeats. Mutational inactivation of the NES, which is 
      not conserved in cIAP2, reduces cIAP1 nuclear export. Forced relocation of cIAP1 
      to the nucleus did not significantly alter its ability to prevent apoptosis. 
      Interestingly, co-expression experiments showed that the cIAP1 and 
      cIAP2-interacting protein TNF receptor-associated factor 2 (TRAF2) plays an 
      important role as regulator of IAP nucleocytoplasmic localization, by preventing 
      nuclear translocation of cIAP1 and cIAP2. TRAF2-mediated cytoplasmic retention of 
      cIAP1 was reduced upon TNFalpha treatment. Our results identify molecular 
      mechanisms that contribute to regulate the subcellular localization of cIAP1 and 
      cIAP2. Translocation between different cell compartments may add a further level 
      of control for cIAP1 and cIAP2 activity.
FAU - Vischioni, Barbara
AU  - Vischioni B
AD  - Department of Medical Oncology, VU University Medical Center, HV1081 Amsterdam, 
      The Netherlands.
FAU - Giaccone, Giuseppe
AU  - Giaccone G
FAU - Span, Simone W
AU  - Span SW
FAU - Kruyt, Frank A E
AU  - Kruyt FA
FAU - Rodriguez, Jose A
AU  - Rodriguez JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (Fatty Acids, Unsaturated)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Karyopherins)
RN  - 0 (Proteins)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.3.2.27 (BIRC2 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - Y031I2N1EO (leptomycin B)
SB  - IM
MH  - Active Transport, Cell Nucleus/genetics
MH  - Amino Acid Sequence
MH  - Apoptosis/drug effects/genetics
MH  - Cell Compartmentation/genetics
MH  - Cell Line, Tumor
MH  - Cell Nucleus/genetics/*metabolism
MH  - Cytoplasm/genetics/*metabolism
MH  - Fatty Acids, Unsaturated
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins
MH  - Karyopherins/genetics/metabolism
MH  - Molecular Sequence Data
MH  - Protein Structure, Tertiary/genetics
MH  - Protein Transport/genetics
MH  - Proteins/genetics/*metabolism
MH  - *Receptors, Cytoplasmic and Nuclear
MH  - Sequence Homology, Amino Acid
MH  - TNF Receptor-Associated Factor 2
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Ubiquitin-Protein Ligases
MH  - Exportin 1 Protein
EDAT- 2004/07/22 05:00
MHDA- 2004/10/05 09:00
CRDT- 2004/07/22 05:00
PHST- 2003/10/15 00:00 [received]
PHST- 2004/03/10 00:00 [revised]
PHST- 2004/07/22 05:00 [pubmed]
PHST- 2004/10/05 09:00 [medline]
PHST- 2004/07/22 05:00 [entrez]
AID - S0014482704002757 [pii]
AID - 10.1016/j.yexcr.2004.04.040 [doi]
PST - ppublish
SO  - Exp Cell Res. 2004 Aug 15;298(2):535-48. doi: 10.1016/j.yexcr.2004.04.040.