MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines.
The MAGE-A, MAGE-B, and MAGE-C protein families comprise the class-I MAGE/cancer testes antigens, a group of highly homologous proteins whose expression is suppressed in all normal tissues except developing sperm. Aberrant expression of class I MAGE proteins occurs in melanomas and many other malignancies, and MAGE proteins have long been recognized as tumor-specific targets; however, their functions have largely been unknown. Here, we show that suppression of class I MAGE proteins induces apoptosis in the Hs-294T, A375, and S91 MAGE-positive melanoma cell lines and that members of all three families of MAGE class I proteins form complexes with KAP1, a scaffolding protein that is known as a corepressor of p53 expression and function. In addition to inducing apoptosis, MAGE suppression decreases KAP1 complexing with p53, increases immunoreactive and acetylated p53, and activates a p53 responsive reporter gene. Suppression of class I MAGE proteins also induces apoptosis in MAGE-A-positive, p53wt/wt parental HCT 116 colon cancer cells but not in a MAGE-A-positive HCT 116 p53-/- variant, indicating that MAGE suppression of apoptosis requires p53. Finally, treatment with MAGE-specific small interfering RNA suppresses S91 melanoma growth in vivo, in syngenic DBA2 mice. Thus, class I MAGE protein expression may suppress apoptosis by suppressing p53 and may actively contribute to the development of malignancies and by promoting tumor survival. Because the expression of class I MAGE proteins is limited in normal tissues, inhibition of MAGE antigen expression or function represents a novel and specific treatment for melanoma and diverse malignancies.
Yang
Bing
B
Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA. byang@dermatology.wisc.edu
O'Herrin
Sean M
SM
Wu
Jianqiang
J
Reagan-Shaw
Shannon
S
Ma
Yongsheng
Y
Bhat
Kumar M R
KM
Gravekamp
Claudia
C
Setaluri
Vijayasaradhi
V
Peters
Noel
N
Hoffmann
F Michael
FM
Peng
Hongzhuang
H
Ivanov
Alexey V
AV
Simpson
Andrew J G
AJ
Longley
B Jack
BJ
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology*; D048708:Cell Growth Processes / Q000276:immunology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D016159:Tumor Suppressor Protein p53 / Q000276:immunology
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C101116:TRIM28 protein, human; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28