MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines

Bing Yang, Sean M. O'Herrin, Jianqiang Wu, Shannon Reagan-Shaw, Yongsheng Ma, Kumar M.R. Bhat, Claudia Gravekamp, Vijayasaradhi Setaluri, Noel Peters, F. Michael Hoffmann, Hongzhuang Peng, Alexey V. Ivanov, Andrew J.G. Simpson, B. Jack Longley

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194 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)9954-9962
Number of pages9
JournalCancer Research
Volume67
Issue number20
DOIs
StatePublished - Oct 15 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yang, B., O'Herrin, S. M., Wu, J., Reagan-Shaw, S., Ma, Y., Bhat, K. M. R., Gravekamp, C., Setaluri, V., Peters, N., Hoffmann, F. M., Peng, H., Ivanov, A. V., Simpson, A. J. G., & Longley, B. J. (2007). MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Research, 67(20), 9954-9962. https://doi.org/10.1158/0008-5472.CAN-07-1478