MAGE-A, mMage-b, and MAGE-C Proteins Form Complexes with KAP1 and Suppress p53-Dependent Apoptosis in MAGE-Positive Cell Lines

Abstract

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-Apositive, p53wt/wt parental HCT 116 colon cancer cells but not in a MAGE-A-positive HCT 116 p53 À/À 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. [Cancer Res 2007;67(20):9954-62]

When MAGE meets RING: insights into biological functions of MAGE proteins

“…Liu et al (2008) reported that overexpression of MAGE-A3 promoted cell proliferation and increased primary tumor size, in an orthotopic xenograft model of thyroid cancer. In addition, treatment with MAGE specific small RNAs suppressed melanoma growth in a xenograft mouse model (Yang et al, 2007). The authors suggested that type I MAGE proteins suppress cancer cell apoptosis by suppressing p53 function and thus promote tumorigenesis and tumor progression.…”

“…Exciting progress in this field was achieved when several groups' data are pointing to RING domain proteins as binding partners for both type I and type II MAGEs (Pebernard et al, 2004;Rual et al, 2005;Sergeant et al, 2005;Yang et al, 2007;Taylor et al, 2008). For example, the interspersed repeat domain of NRAGE/MAGE-D1 (herein referred to as MAGE-D1 for simplicity) was identified to bind RING domain protein XIAP and the avian IAP homolog ITA, members of the inhibitor of apoptosis (IAP) family (Jordan et al, 2001).…”

“…In addition, the authors also detected the interaction between Praja1 and NECDIN, another member of type II MAGEs. As for type I MAGEs, Yang et al (2007) suggested that members of all three subfamilies of type I MAGEs form complexes with KAP1/TRIM28 (referred to as TRIM28 hereafter), which is a co-repressor of p53. A genome-wide yeast two-hybrid study has also identified several pairs of binding partners between MAGEs and RING domain proteins (Rual et al, 2005).…”

L’intrusion des régulateurs de l’épigénome mâle dans les cellules somatiques cancéreuses

“…En effet, il a été montré que la suppression de l'expression des MAGE de classe I (membres exprimés normalement uniquement dans les cellules germinales) induit l'apoptose des lignées cellulaires issues de mélanomes, positives pour l'expression illégitime des MAGE. Des études supplémentaires ont montré que cette résistance à l'apoptose était associée à une action neutralisante des MAGE sur P53 [16]. En accord avec ces données, une autre étude a montré que MAGE-A2, un membre de la même famille, recrute l'histone-déacé-tylase 3 (HDAC3) et cible P53, et s'oppose ainsi à l'acétylation et à l'activation de P53 à la suite d'un traitement génotoxique [17].…”

Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX

“…Importantly, CT antigens belonging to the melanoma-associated antigen (MAGE) A, B and C family seem to be involved in oncogenesis, providing protection against apoptosis in tumor cells. 3 The expression of other tumor antigens, such as 'overexpression' antigens p53 and HER-2/neu, or 'differentiation antigens' gp100 and Mart-1, is less restricted to tumor cells and their use for cancer-drug targeting may be associated with negative side effects.…”