Regulation of the stability of P-glycoprotein by ubiquitination

Zhigang Zhang, Jin Ying Wu, William N. Hait, Jin Ming Yang

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Ubiquitination plays a crucial role in regulating protein turnover. Here we show that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance. We found that P-glycoprotein was constitutively ubiquitinated in drug-resistant cancer cells. Transfection of multidrug-resistant cells with wild-type ubiquitin or treatment with an N-glycosylation inhibitor increased the ubiquitination of P-glycoprotein and increased P-glycoprotein degradation. Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132), a proteasome inhibitor, induced accumulation of ubiquitinated P-glycoprotein, suggesting the involvement of the proteasome in the turnover of the transporter. Treatment of multidrug-resistant cells with 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester that increases the phosphorylation of P-glycoprotein through activation of protein kinase C, or substituting phosphorylation sites of P-glycoprotein by nonphosphorylatable residues did not affect the ubiquitination of the transporter. Enhanced ubiquitination of P-glycoprotein resulted in a decrease of the function of the transporter, as demonstrated by increased intracellular drug accumulation and increased cellular sensitivity to drugs transported by P-glycoprotein. Our results indicate that the stability and function of P-glycoprotein can be regulated by the ubiquitin-proteasome pathway and suggest that modulating the ubiquitination of P-glycoprotein might be a novel approach to the reversal of drug resistance.

Original languageEnglish (US)
Pages (from-to)395-403
Number of pages9
JournalMolecular pharmacology
Volume66
Issue number3
DOIs
StatePublished - Sep 2004

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Regulation of the stability of P-glycoprotein by ubiquitination'. Together they form a unique fingerprint.

Cite this