MAGE-A1 interacts with adaptor SKIP and the deacetylase HDAC1 to repress transcription.
MAGE-A1 belongs to a family of 12 genes that are active in various types of tumors and silent in normal tissues except in male germ-line cells. The MAGE-encoded antigens recognized by T cells are highly tumor-specific targets for T cell-oriented cancer immunotherapy. The function of MAGE-A1 is currently unknown. To analyze it, we attempted to identify protein partners of MAGE-A1. Using yeast two-hybrid screening, we detected an interaction between MAGE-A1 and Ski Interacting Protein (SKIP). SKIP is a transcriptional regulator that connects DNA-binding proteins to proteins that either activate or repress transcription. We show that MAGE-A1 inhibits the activity of a SKIP-interacting transactivator, namely the intracellular part of Notch1. Deletion analysis indicated that this inhibition requires the binding of MAGE-A1 to SKIP. Moreover, MAGE-A1 was found to actively repress transcription by binding and recruiting histone deacetylase 1 (HDAC1). Our results indicate that by binding to SKIP and by recruiting HDACs, MAGE-A1 can act as a potent transcriptional repressor. MAGE-A1 could therefore participate in the setting of specific gene expression patterns for tumor cell growth or spermatogenesis.
Laduron
Sandra
S
Ludwig Institute for Cancer Research, Brussels branch, and Cellular Genetics Unit, Université Catholique de Louvain, Brussels B1200, Belgium.
Deplus
Rachel
R
Zhou
Sifang
S
Kholmanskikh
Olga
O
Godelaine
Danièle
D
De Smet
Charles
C
Hayward
S Diane
SD
Fuks
François
F
Boon
Thierry
T
De Plaen
Etienne
E
D000818:Animals; D000951:Antigens, Neoplasm; D019556:COS Cells; D002522:Chlorocebus aethiops; D020868:Gene Silencing; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D056918:Nuclear Receptor Coactivators; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D000951:Antigens, Neoplasm; D058950:Melanoma-Specific Antigens; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056918:Nuclear Receptor Coactivators; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C111791:SNW1 protein, human; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases