RSK1 protects P-glycoprotein/ABCB1 against ubiquitin-proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1

Kazuhiro Katayama, Chiaki Fujiwara, Kohji Noguchi, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

P-glycoprotein (P-gp) is a critical determinant of multidrug resistance in cancer. We previously reported that MAPK inhibition downregulates P-gp expression and that P-gp undergoes ubiquitin-proteasomal degradation regulated by UBE2R1 and SCFFbx15. Here, we investigated the crosstalk between MAPK inhibition and the ubiquitin-proteasomal degradation of P-gp. Proteasome inhibitors or knockdown of FBXO15 and/or UBE2R1 cancelled MEK inhibitor-induced P-gp downregulation. RSK1 phosphorylated Thr162 on UBE2R1 but did not phosphorylate FBXO15. MEK and RSK inhibitors increased UBE2R1-WT but not UBE2R1-T162D and -T162A expression. UBE2R1-T162D showed higher self-ubiquitination and destabilisation than UBE2R1-WT and -T162A. Unlike UBE2R1-WT and -T162A, UBE2R1-T162D did not induce P-gp ubiquitination. UBE2R1-WT or -T162A downregulated P-gp expression and upregulated rhodamine 123 level and sensitivity to vincristine and doxorubicin. However, UBE2R1-T162D did not confer any change in P-gp expression, rhodamine 123 accumulation and sensitivity to the drugs. These results suggest that RSK1 protects P-gp against ubiquitination by reducing UBE2R1 stability.

Original languageEnglish
Article number36134
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Oct 27

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Ubiquitin-Conjugating Enzymes
P-Glycoprotein
Ubiquitin
Down-Regulation
Ubiquitination
Rhodamine 123
Mitogen-Activated Protein Kinase Kinases
Proteasome Inhibitors
Multiple Drug Resistance
Vincristine
Doxorubicin

ASJC Scopus subject areas

  • General

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RSK1 protects P-glycoprotein/ABCB1 against ubiquitin-proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1. / Katayama, Kazuhiro; Fujiwara, Chiaki; Noguchi, Kohji; Sugimoto, Yoshikazu.

In: Scientific Reports, Vol. 6, 36134, 27.10.2016.

Research output: Contribution to journalArticle

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