PMID- 10097128
OWN - NLM
STAT- MEDLINE
DCOM- 19990512
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 7
DP  - 1999 Mar 30
TI  - Ubiquitin-dependent degradation of IkappaBalpha is mediated by a ubiquitin ligase
      Skp1/Cul 1/F-box protein FWD1.
PG  - 3859-63
AB  - Activation of the transcription factor nuclear factor kappa B (NF-kappaB) is
      controlled by proteolysis of its inhibitory subunit (IkappaB) via the
      ubiquitin-proteasome pathway. Signal-induced phosphorylation of IkappaBalpha by a
      large multisubunit complex containing IkappaB kinases is a prerequisite for
      ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/betaTrCP), a 
      member of the F-box/WD40-repeat proteins, is associated specifically with
      IkappaBalpha only when IkappaBalpha is phosphorylated. The introduction of FWD1
      into cells significantly promotes ubiquitination and degradation of IkappaBalpha 
      in concert with IkappaB kinases, resulting in nuclear translocation of NF-kappaB.
      In addition, FWD1 strikingly evoked the ubiquitination of IkappaBalpha in the in 
      vitro system. In contrast, a dominant-negative form of FWD1 inhibits the
      ubiquitination, leading to stabilization of IkappaBalpha. These results suggest
      that the substrate-specific degradation of IkappaBalpha is mediated by a
      Skp1/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWD1
      serves as an intracellular receptor for phosphorylated IkappaBalpha.
      Skp1/Cullin/F-box protein FWD1 might play a critical role in transcriptional
      regulation of NF-kappaB through control of IkappaB protein stability.
FAU - Hatakeyama, S
AU  - Hatakeyama S
AD  - Department of Molecular and Cellular Biology, Medical Institute of Bioregulation,
      Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
FAU - Kitagawa, M
AU  - Kitagawa M
FAU - Nakayama, K
AU  - Nakayama K
FAU - Shirane, M
AU  - Shirane M
FAU - Matsumoto, M
AU  - Matsumoto M
FAU - Hattori, K
AU  - Hattori K
FAU - Higashi, H
AU  - Higashi H
FAU - Nakano, H
AU  - Nakano H
FAU - Okumura, K
AU  - Okumura K
FAU - Onoe, K
AU  - Onoe K
FAU - Good, R A
AU  - Good RA
FAU - Nakayama, K
AU  - Nakayama K
LA  - eng
SI  - GENBANK/AF081887
SI  - GENBANK/AF083214
SI  - GENBANK/AF083215
SI  - GENBANK/AF083216
GR  - AG05628-14/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
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 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Recombinant Proteins)
RN  - 0 (S-Phase Kinase-Associated Proteins)
RN  - 0 (Ubiquitins)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Cycle Proteins/chemistry/*metabolism
MH  - Cell Line
MH  - DNA-Binding Proteins/*metabolism
MH  - Drosophila melanogaster
MH  - HeLa Cells
MH  - Humans
MH  - *I-kappa B Proteins
MH  - Mice
MH  - Molecular Sequence Data
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/antagonists & inhibitors
MH  - Phosphorylation
MH  - Recombinant Proteins/chemistry/metabolism
MH  - S-Phase Kinase-Associated Proteins
MH  - Sequence Alignment
MH  - Sequence Homology, Amino Acid
MH  - Transfection
MH  - Ubiquitins/*metabolism
MH  - Xenopus laevis
PMC - PMC22385
EDAT- 1999/03/31 00:00
MHDA- 1999/03/31 00:01
CRDT- 1999/03/31 00:00
PHST- 1999/03/31 00:00 [pubmed]
PHST- 1999/03/31 00:01 [medline]
PHST- 1999/03/31 00:00 [entrez]
AID - 10.1073/pnas.96.7.3859 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3859-63. doi: 10.1073/pnas.96.7.3859.