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Author Notes:

To whom correspondence should be addressed (etmorga@emory.edu).

H.S. and C-M.L. contributed equally to this work.

Haiyan Sun, Choon-myung Lee and Shweta Tripathi performed the experiments.

Kyung-bo Kim provided the immunoproteasome inhibitors.

Edward Morgan, Haiyan Sun and Choon-myung Lee drafted the paper.

All authors contributed to the design of the experiments and to the critical review of the paper prior to submission.

Abbreviations used: CT-L, chymotrypsin-like; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN, interferon; IL-1, interleukin-1β; LMP, large multifunctional peptidase; L-NAME, N G-nitro-L-arginine methyl ester; NF-κB, nuclear factor κB; NOS2, inducible nitric oxide synthase; NOx, nitrate and nitrite; P450, cytochrome P450; PB, phenobarbital.

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Research Funding:

This work was supported by the National Institutes of Health [grant numbers GM069971 (to E.T.M.) and CA131059 (to K-B.K.)] and by the 2011 Natural Science Foundation of Guangdong Province, China [grant number S2011010004456].

Keywords:

  • cytochrome P450
  • immunoproteasome
  • interleukin-1 (IL-1)
  • nitric oxide (NO)
  • proteasome

Nitric oxide-dependent CYP2B degradation is potentiated by a cytokine-regulated pathway and utilizes the immunoproteasome subunit LMP2

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Journal Title:

Biochemical Journal

Volume:

Volume 2012, Number 445

Publisher:

, Pages 377-382

Type of Work:

Article | Final Publisher PDF

Abstract:

CYP2B proteins in rat hepatocytes undergo NO-dependent proteolytic degradation, but the mechanisms and the reasons for the specificity towards only certain P450 enzymes are yet unknown. Here, we found that down-regulation of CYP2B proteins by the NO donor NOC-18 is accelerated by pretreatment of the hepatocytes with interleukin-1β (IL-1) in the presence of a nitric oxide synthase inhibitor, suggesting that an NO-independent action of IL-1 contributes to the lability of CYP2B proteins. The immunoproteasome subunit LMP2 was significantly expressed in hepatocytes under basal conditions, and IL-1 induced LMP2 within 6–12 h of treatment. CYP2B protein degradation in response to IL-1 was attenuated by the selective LMP2 inhibitor UK-101, but not by the LMP7 inhibitor IPSI. The results show that LMP2 contributes to the NO-dependent degradation of CYP2B proteins, and suggest that induction of LMP2 may be involved in the potentiation of this degradation by IL-1.

Copyright information:

© 2012 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 2.5 Generic License (http://creativecommons.org/licenses/by-nc/2.5/).

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