PMID- 10574930
OWN - NLM
STAT- MEDLINE
DCOM- 20000203
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 49
DP  - 1999 Dec 3
TI  - Immunosuppressant FK506 activates NF-kappaB through the proteasome-mediated
      degradation of IkappaBalpha. Requirement for Ikappabalpha n-terminal
      phosphorylation but not ubiquitination sites.
PG  - 34657-62
AB  - The immunosuppressant FK506 activates NF-kappaB through IkappaBalpha degradation 
      in nonlymphoid cells. In the present study, we analyzed mechanisms by which FK506
      induces IkappaBalpha degradation. We found that FK506 induces the degradation of 
      both IkappaBalpha and IkappaBbeta and that the time courses of the FK506-induced 
      degradation are quite different from degradation induced by interleukin 1 (IL-1).
      Despite this difference, FK506-induced IkappaBalpha degradation was dependent on 
      the N-terminal Ser-32 and Ser-36 phosphorylation sites and was mediated by
      proteasomes, as is the case for IL-1-induced IkappaBalpha degradation. We further
      showed that FK506 induces weak and slow phosphorylation of IkappaBalpha at
      Ser-32. However, unlike IL-1-induced degradation, IKK-1 and IKK-2 were not
      activated significantly nor was FK506-induced IkappaBalpha degradation dependent 
      on the N-terminal ubiquitination sites (Lys-21 and Lys-22). These results
      therefore indicate that FK506 and IL-1 utilize similar but distinct mechanisms to
      induce the phosphorylation and degradation of IkappaBalpha.
FAU - Zhang, Y
AU  - Zhang Y
AD  - Department of Molecular Pathology, Cancer Research Institute, Kanazawa
      University, Kanazawa 920-0934, Japan.
FAU - Sun, X
AU  - Sun X
FAU - Muraoka, K
AU  - Muraoka K
FAU - Ikeda, A
AU  - Ikeda A
FAU - Miyamoto, S
AU  - Miyamoto S
FAU - Shimizu, H
AU  - Shimizu H
FAU - Yoshioka, K
AU  - Yoshioka K
FAU - Yamamoto, K
AU  - Yamamoto K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (I kappa B beta protein)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-1)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Ubiquitins)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 452VLY9402 (Serine)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (CHUK protein, human)
RN  - EC 2.7.11.10 (Chuk protein, mouse)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.10 (IKBKB protein, human)
RN  - EC 2.7.11.10 (IKBKE protein, human)
RN  - EC 2.7.11.10 (Ikbkb protein, mouse)
RN  - EC 2.7.11.10 (Ikbke protein, mouse)
RN  - K3Z4F929H6 (Lysine)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Humans
MH  - I-kappa B Kinase
MH  - *I-kappa B Proteins
MH  - Immunosuppressive Agents/*metabolism
MH  - Interleukin-1/pharmacology
MH  - Luciferases/metabolism
MH  - Lysine/metabolism
MH  - Mice
MH  - Molecular Sequence Data
MH  - Mutation
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/*metabolism
MH  - Phosphorylation/drug effects
MH  - Plasmids
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - Serine/metabolism
MH  - Tacrolimus/*metabolism/pharmacology
MH  - Time Factors
MH  - Transcriptional Activation/drug effects
MH  - Transfection
MH  - Ubiquitins/*metabolism
EDAT- 1999/11/27 00:00
MHDA- 1999/11/27 00:01
CRDT- 1999/11/27 00:00
PHST- 1999/11/27 00:00 [pubmed]
PHST- 1999/11/27 00:01 [medline]
PHST- 1999/11/27 00:00 [entrez]
AID - 10.1074/jbc.274.49.34657 [doi]
AID - S0021-9258(19)53373-7 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Dec 3;274(49):34657-62. doi: 10.1074/jbc.274.49.34657.