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Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential

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Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential. / García-Piñeres, A J; Lindenmeyer, M T; Merfort, I.

In: LIFE SCI, Vol. 75, No. 7, 02.07.2004, p. 841-56.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

García-Piñeres, AJ, Lindenmeyer, MT & Merfort, I 2004, 'Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential', LIFE SCI, vol. 75, no. 7, pp. 841-56. https://doi.org/10.1016/j.lfs.2004.01.024

APA

García-Piñeres, A. J., Lindenmeyer, M. T., & Merfort, I. (2004). Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential. LIFE SCI, 75(7), 841-56. https://doi.org/10.1016/j.lfs.2004.01.024

Vancouver

García-Piñeres AJ, Lindenmeyer MT, Merfort I. Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential. LIFE SCI. 2004 Jul 2;75(7):841-56. https://doi.org/10.1016/j.lfs.2004.01.024

Bibtex

@article{a438c80863764aa59de6f13ebb485842,
title = "Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential",
abstract = "Sesquiterpene lactones (SLs) are potent anti-inflammatory substances. It was previously shown that the anti-inflammatory effect could be partly explained by the inhibition of the transcription factor NF-kappaB. Whether they inhibit the DNA binding of NF-kappaB, the activation of the IkappaB-kinase, or both is still a matter of debate. The data supporting these hypotheses were obtained using different cell systems. In this contribution we analyzed the mechanism of the sesquiterpene lactone-mediated inhibition using different cell systems, and showed that in all the cell lines analyzed, SLs inhibited both NF-kappaB binding and the IkappaB-kinase, but that the former played a more preponderant role in the inhibition. These results again confirm the importance of cysteine 38 in the inhibition and regulation of NF-kappaB's function. Moreover, we compared the selectivity of the SL parthenolide with that of N-ethyl maleimide (NEM). We showed that NEM directly alkylated p65 as well as p50 of NF-kappaB, whereas SLs possess a selectivity towards p65. Finally, we studied the transactivating properties of various p65 mutants, to analyze the effect of exchanged cysteine residues in the DNA binding domain of NF-kappaB/p65 on its function and demonstrated that the transactivating potential of the mutants did not correlate with their DNA binding strenght.",
keywords = "Animals, Anti-Inflammatory Agents, Non-Steroidal, Calcium-Binding Proteins, Cysteine, DNA-Binding Proteins, Ethylmaleimide, HeLa Cells, Humans, I-kappa B Kinase, Jurkat Cells, Macrophages, Membrane Glycoproteins, Mice, Mutation, NF-kappa B, Nerve Tissue Proteins, Protein-Serine-Threonine Kinases, Sesquiterpenes, Synaptotagmin I, Synaptotagmins, Transcription Factor RelA, Transcriptional Activation, Transfection, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't",
author = "Garc{\'i}a-Pi{\~n}eres, {A J} and Lindenmeyer, {M T} and I Merfort",
note = "Copyright 2004 Elsevier Inc.",
year = "2004",
month = jul,
day = "2",
doi = "10.1016/j.lfs.2004.01.024",
language = "English",
volume = "75",
pages = "841--56",
journal = "LIFE SCI",
issn = "0024-3205",
publisher = "Elsevier Inc.",
number = "7",

}

RIS

TY - JOUR

T1 - Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential

AU - García-Piñeres, A J

AU - Lindenmeyer, M T

AU - Merfort, I

N1 - Copyright 2004 Elsevier Inc.

PY - 2004/7/2

Y1 - 2004/7/2

N2 - Sesquiterpene lactones (SLs) are potent anti-inflammatory substances. It was previously shown that the anti-inflammatory effect could be partly explained by the inhibition of the transcription factor NF-kappaB. Whether they inhibit the DNA binding of NF-kappaB, the activation of the IkappaB-kinase, or both is still a matter of debate. The data supporting these hypotheses were obtained using different cell systems. In this contribution we analyzed the mechanism of the sesquiterpene lactone-mediated inhibition using different cell systems, and showed that in all the cell lines analyzed, SLs inhibited both NF-kappaB binding and the IkappaB-kinase, but that the former played a more preponderant role in the inhibition. These results again confirm the importance of cysteine 38 in the inhibition and regulation of NF-kappaB's function. Moreover, we compared the selectivity of the SL parthenolide with that of N-ethyl maleimide (NEM). We showed that NEM directly alkylated p65 as well as p50 of NF-kappaB, whereas SLs possess a selectivity towards p65. Finally, we studied the transactivating properties of various p65 mutants, to analyze the effect of exchanged cysteine residues in the DNA binding domain of NF-kappaB/p65 on its function and demonstrated that the transactivating potential of the mutants did not correlate with their DNA binding strenght.

AB - Sesquiterpene lactones (SLs) are potent anti-inflammatory substances. It was previously shown that the anti-inflammatory effect could be partly explained by the inhibition of the transcription factor NF-kappaB. Whether they inhibit the DNA binding of NF-kappaB, the activation of the IkappaB-kinase, or both is still a matter of debate. The data supporting these hypotheses were obtained using different cell systems. In this contribution we analyzed the mechanism of the sesquiterpene lactone-mediated inhibition using different cell systems, and showed that in all the cell lines analyzed, SLs inhibited both NF-kappaB binding and the IkappaB-kinase, but that the former played a more preponderant role in the inhibition. These results again confirm the importance of cysteine 38 in the inhibition and regulation of NF-kappaB's function. Moreover, we compared the selectivity of the SL parthenolide with that of N-ethyl maleimide (NEM). We showed that NEM directly alkylated p65 as well as p50 of NF-kappaB, whereas SLs possess a selectivity towards p65. Finally, we studied the transactivating properties of various p65 mutants, to analyze the effect of exchanged cysteine residues in the DNA binding domain of NF-kappaB/p65 on its function and demonstrated that the transactivating potential of the mutants did not correlate with their DNA binding strenght.

KW - Animals

KW - Anti-Inflammatory Agents, Non-Steroidal

KW - Calcium-Binding Proteins

KW - Cysteine

KW - DNA-Binding Proteins

KW - Ethylmaleimide

KW - HeLa Cells

KW - Humans

KW - I-kappa B Kinase

KW - Jurkat Cells

KW - Macrophages

KW - Membrane Glycoproteins

KW - Mice

KW - Mutation

KW - NF-kappa B

KW - Nerve Tissue Proteins

KW - Protein-Serine-Threonine Kinases

KW - Sesquiterpenes

KW - Synaptotagmin I

KW - Synaptotagmins

KW - Transcription Factor RelA

KW - Transcriptional Activation

KW - Transfection

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.lfs.2004.01.024

DO - 10.1016/j.lfs.2004.01.024

M3 - SCORING: Journal article

C2 - 15183076

VL - 75

SP - 841

EP - 856

JO - LIFE SCI

JF - LIFE SCI

SN - 0024-3205

IS - 7

ER -