Methylation-controlled J protein promotes c-Jun degradation to prevent ABCB1 transporter expression.
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.
Hatle
Ketki M
KM
Department of Medicine/Immunobiology Program, Given Medical Building D-305, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405, USA.
Neveu
Wendy
W
Dienz
Oliver
O
Rymarchyk
Stacia
S
Barrantes
Ramiro
R
Hale
Sarah
S
Farley
Nicholas
N
Lounsbury
Karen M
KM
Bond
Jeffrey P
JP
Taatjes
Douglas
D
Rincón
Mercedes
M
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000648:ultrastructure; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014714:Vertebrates
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C519405:DNAJC15 protein, human; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D027361:Organic Anion Transporters; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger