Protein phosphatase 2A regulates cytotoxicity and drug resistance by dephosphorylating AHR and MDR1

Liping Chen, Ping Guo, Wenxue Li, Xinhang Jiang, Qun Zhao, Daochuan Li, Qing Wang, Yongmei Xiao, Xiumei Xing, Yaqin Pang, Michael Aschner, Lihua Zhang, Wen Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Protein phosphatase 2A (PP2A) is a serine/threonine dephosphorylating enzyme complex that plays numerous roles in biological processes, including cell growth and metabolism. However, its specific actions in many of these critical pathways are unclear. To explore mechanisms underlying metabolic enzyme regulation in the liver, we investigated the key pathways involved in regulation of xenobiotic-metabolizing enzymes in a mouse model with hepatocyte-specific deletion of Ppp2r1a, encoding the Aα subunit of PP2A. We performed transcriptome and phosphoproteome analysis in mouse livers at the age of 3 months and identified 2695 differentially expressed genes and 549 upregulated phosphoproteins in homozygous knockout mouse livers compared with WT littermates. In particular, the expression of metabolic enzymes Cyp2e1, Cyp1a1, Cyp1a2, Mdr1a, and Abcg2 was dramatically altered in homozygous knockout mouse livers. We also demonstrated that activation of PP2A reversed the decline of metabolic enzyme expression in primary mouse hepatocytes. We found that specific PP2A holoenzymes were involved in metabolic enzyme induction through dephosphorylation of transcription factors, nuclear receptors, or the target enzymes themselves, leading to dysregulation of xenobiotic metabolism or drug-induced hepatotoxicity. Notably, we confirmed that a regulatory axis, PP2A B56α–aryl hydrocarbon receptor–Cyp1a1, was involved in benzo(a) pyrene-induced cytotoxicity through dephosphorylation of the metabolic nuclear receptor, aryl hydrocarbon receptor, at serine 36. In addition, we showed that PP2A B56δ complexes directly dephosphorylated the multidrug efflux pump MDR1 (encoded by multi-drug resistance gene 1), contributing to drug resistance against the chemotherapeutic 5-fluorouracil. Taken together, these novel findings demonstrate the involvement of PP2A in the regulation of liver metabolism.

Original languageEnglish (US)
Article number101918
JournalJournal of Biological Chemistry
Volume298
Issue number5
DOIs
StatePublished - May 1 2022

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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