PMID- 10655476
OWN - NLM
STAT- MEDLINE
DCOM- 20000302
LR  - 20220317
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 3
DP  - 2000 Feb 1
TI  - A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha
      controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes.
PG  - 1014-9
AB  - Appropriate subcellular localization is crucial for regulation of NF-kappaB
      function. Herein, we show that latent NF-kappaB complexes can enter and exit the 
      nucleus in preinduction states. The nuclear export inhibitor leptomycin B (LMB)
      sequestered NF-kappaB/IkappaBalpha complexes in the nucleus. Using deletion and
      site-directed mutagenesis, we identified a previously uncharacterized nuclear
      export sequence in residues 45-54 of IkappaBalpha that was required for
      cytoplasmic localization of inactive complexes. This nuclear export sequence also
      caused nuclear exclusion of heterologous proteins in a LMB-sensitive manner.
      Importantly, a LMB-insensitive CRM1 mutant (Crm1-K1) abolished LMB-induced
      nuclear accumulation of the inactive complexes. Moreover, a cell-permeable p50
      NF-kappaB nuclear localization signal peptide also blocked these LMB effects.
      These results suggest that NF-kappaB/IkappaBalpha complexes shuttle between the
      cytoplasm and nucleus by a nuclear localization signal-dependent nuclear import
      and a CRM1-dependent nuclear export. The LMB-induced nuclear complexes could not 
      bind DNA and were inaccessible to signaling events, because LMB inhibited
      NF-kappaB activation without affecting the subcellular localization of upstream
      kinases IKKbeta and NIK. Our findings indicate that the dominant nuclear export
      over nuclear import contributes to the largely cytoplasmic localization of the
      inactive complexes to achieve efficient NF-kappaB activation by extracellular
      signals.
FAU - Huang, T T
AU  - Huang TT
AD  - Program in Molecular and Cellular Pharmacology, Department of Pharmacology,
      University of Wisconsin, K4/554 Clinical Sciences Center, 600 Highland Avenue,
      Madison, WI 53792, USA.
FAU - Kudo, N
AU  - Kudo N
FAU - Yoshida, M
AU  - Yoshida M
FAU - Miyamoto, S
AU  - Miyamoto S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Fatty Acids, Unsaturated)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Karyopherins)
RN  - 0 (Macromolecular Substances)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Protein Sorting Signals)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (exportin 1 protein)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 9007-49-2 (DNA)
RN  - Y031I2N1EO (leptomycin B)
SB  - IM
MH  - Amino Acid Motifs
MH  - Animals
MH  - Biological Transport/drug effects
MH  - COS Cells
MH  - Carrier Proteins/physiology
MH  - Cell Nucleus/metabolism
MH  - Chlorocebus aethiops
MH  - Cytoplasm/*metabolism
MH  - DNA/metabolism
MH  - DNA-Binding Proteins/*chemistry/genetics/physiology
MH  - Fatty Acids, Unsaturated/pharmacology
MH  - HeLa Cells
MH  - Humans
MH  - *I-kappa B Proteins
MH  - *Karyopherins
MH  - Macromolecular Substances
MH  - Models, Biological
MH  - Mutagenesis, Site-Directed
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/*metabolism
MH  - Protein Sorting Signals/chemistry/*physiology
MH  - *Receptors, Cytoplasmic and Nuclear
MH  - Recombinant Fusion Proteins/metabolism
MH  - Signal Transduction
MH  - Transcription, Genetic
MH  - Transfection
PMC - PMC15505
EDAT- 2000/02/03 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/02/03 09:00
PHST- 2000/02/03 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/03 09:00 [entrez]
AID - 10.1073/pnas.97.3.1014 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1014-9. doi: 10.1073/pnas.97.3.1014.