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.
Ludwig Institute for Cancer Research, Brussels branch, and Cellular Genetics Unit, Université Catholique de Louvain, Brussels B1200, Belgium.
Sandra
S
Laduron
Rachel
R
Deplus
Sifang
S
Zhou
Olga
O
Kholmanskikh
Danièle
D
Godelaine
Charles
C
De Smet
S Diane
SD
Hayward
François
F
Fuks
Thierry
T
Boon
Etienne
E
De Plaen
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