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Molecular and Cellular Biology, April 2007, p. 2952-2966, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01804-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Methylation-Controlled J Protein Promotes c-Jun Degradation To Prevent ABCB1 Transporter Expression{triangledown} ,{dagger}

Ketki M. Hatle,1 Wendy Neveu,1 Oliver Dienz,1 Stacia Rymarchyk,1 Ramiro Barrantes,2 Sarah Hale,3 Nicholas Farley,1 Karen M. Lounsbury,3 Jeffrey P. Bond,2 Douglas Taatjes,4 and Mercedes Rincón1*

Immunobiology Program, Department of Medicine,1 Department of Microbiology and Molecular Genetics-Bioinformatics,2 Department of Pharmacology,3 Department of Pathology and Microscopy Imaging Center, University of Vermont, Burlington, Vermont 054054

Received 22 September 2006/ Returned for modification 20 October 2006/ Accepted 24 January 2007

Methylation-controlled J protein (MCJ) is a newly identified member of the DnaJ family of cochaperones. Hypermethylation-mediated transcriptional silencing of the MCJ gene has been associated with increased chemotherapeutic resistance in ovarian cancer. However, the biology and function of MCJ remain unknown. Here we show that MCJ is a type II transmembrane cochaperone localized in the Golgi network and present only in vertebrates. MCJ is expressed in drug-sensitive breast cancer cells but not in multidrug-resistant cells. The inhibition of MCJ expression increases resistance to specific drugs by inducing expression of the ABCB1 drug transporter that prevents intracellular drug accumulation. The induction of ABCB1 gene expression is mediated by increased levels of c-Jun due to an impaired degradation of this transcription factor in the absence of MCJ. Thus, MCJ is required in these cells to prevent c-Jun-mediated expression of ABCB1 and maintain drug response.

* Corresponding author. Mailing address: Department of Medicine/Immunobiology Program, Given Medical Building D-305, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405. Phone: (802) 656-0937. Fax: (802) 656-3854. E-mail: mrincon{at}uvm.edu

{triangledown} Published ahead of print on 5 February 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2007, p. 2952-2966, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01804-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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