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PMID: 7809113 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 91 ·No. 26 ·1994-12-20 ·Pages 12740-4

Miyamoto S, Maki M, Schmitt MJ, Hatanaka M, Verma IM

Abstract

Activation of the NF-kappa B/Rel family of transcription factors is regulated by a cytoplasmic inhibitor, I kappa B alpha. Activity of I kappa B alpha is in turn modulated by phosphorylation and proteolysis. It has been postulated that phosphorylation of I kappa B alpha leads to its dissociation from NF-kappa B, and free I kappa B alpha is targeted for rapid degradation. However, this phosphorylation-mediated dissociation event has not been demonstrated in vivo. We demonstrate that, contrary to this hypothesis, phosphorylation of I kappa B alpha induced by tumor necrosis factor alpha in HeLa cells does not induce dissociation. We propose a model in which (i) induced phosphorylation of I kappa B alpha does not result in its dissociation from NF-kappa B, (ii) phosphorylation of I kappa B alpha serves as a signal for degradation, and (iii) degradation of I kappa B alpha occurs while it is still complexed with NF-kappa B.

MeSH Terms
Calpain/antagonists & inhibitors DNA-Binding Proteins/metabolism HeLa Cells Humans I-kappa B Proteins In Vitro Techniques Macromolecular Substances NF-KappaB Inhibitor alpha NF-kappa B/antagonists & inhibitors,metabolism Phosphoproteins/metabolism Phosphorylation Protein Binding Signal Transduction Tumor Necrosis Factor-alpha/pharmacology
Chemicals
DNA-Binding Proteins I-kappa B Proteins Macromolecular Substances NF-kappa B NFKBIA protein, human Phosphoproteins Tumor Necrosis Factor-alpha NF-KappaB Inhibitor alpha Calpain
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Miyamoto S
Molecular Biology and Virology Laboratory, Salk Institute, San Diego, CA 92186-5800.
Maki M
Schmitt M J
Hatanaka M
Verma I M
References (21)
21 references, click to expand
  1. Direct association of pp40/I kappa B beta with rel/NF-kappa B transcription factors: role of ankyrin repeats in the inhibition of DNA binding activity.
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4333-7 PMID: 1533932
  2. PEST sequences are signals for rapid intracellular proteolysis.
    Semin Cell Biol. 1990 Dec;1(6):433-40 PMID: 2103894
  3. I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B p65 and requires the transactivation domain to inhibit NF-kappa B p65 DNA binding.
    Mol Biol Cell. 1992 Dec;3(12):1339-52 PMID: 1493333
  4. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system.
    Int Rev Cytol. 1993;143:1-62 PMID: 8449662
  5. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway.
    Science. 1993 Mar 26;259(5103):1912-5 PMID: 8096091
  6. Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation.
    Mol Cell Biol. 1993 Jun;13(6):3301-10 PMID: 8497253
  7. The p65 subunit of NF-kappa B regulates I kappa B by two distinct mechanisms.
    Genes Dev. 1993 Jul;7(7A):1266-76 PMID: 8319912
  8. Common structural constituents confer I kappa B activity to NF-kappa B p105 and I kappa B/MAD-3.
    EMBO J. 1993 Jul;12(7):2781-8 PMID: 8334994
  9. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B.
    Nature. 1993 Sep 9;365(6442):182-5 PMID: 8371761
  10. Autoregulation of I kappa B alpha activity.
    Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):28-32 PMID: 8278379
  11. Autoregulation of the NF-kappa B transactivator RelA (p65) by multiple cytoplasmic inhibitors containing ankyrin motifs.
    Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1346-50 PMID: 8108414
  12. Comparison of the effect of calpain inhibitors on two extralysosomal proteinases: the multicatalytic proteinase complex and m-calpain.
    J Neurochem. 1994 May;62(5):1989-94 PMID: 8158145
  13. Qualitative changes in the subunit composition of kappa B-binding complexes during murine B-cell differentiation.
    Proc Natl Acad Sci U S A. 1994 May 24;91(11):5056-60 PMID: 8197184
  14. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B.
    Cell. 1994 Sep 9;78(5):773-85 PMID: 8087845
  15. An inducible transcription factor activates expression of human immunodeficiency virus in T cells.
    Nature. 1987 Apr 16-22;326(6114):711-3 PMID: 3031512
  16. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor.
    Cell. 1988 Apr 22;53(2):211-7 PMID: 3129195
  17. I kappa B: a specific inhibitor of the NF-kappa B transcription factor.
    Science. 1988 Oct 28;242(4878):540-6 PMID: 3140380
  18. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B.
    Nature. 1990 Apr 12;344(6267):678-82 PMID: 2157987
  19. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits.
    Biochim Biophys Acta. 1991 Apr 16;1072(1):63-80 PMID: 2018779
  20. Calcium-activated neutral protease (calpain) system: structure, function, and regulation.
    Physiol Rev. 1991 Jul;71(3):813-47 PMID: 2057527
  21. I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention.
    Genes Dev. 1992 Oct;6(10):1899-913 PMID: 1340770
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.91.26.12740
Published
1994-12-20
Pages
12740-4
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC45515
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.91.26.12740 PMC Full Text View journal details
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