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

Research output: Contribution to journalArticle

192 Citations (Scopus)

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

Fingerprint

Protein C
Apoptosis
Cell Line
Proteins
Melanoma
Neoplasms
Antigens
Co-Repressor Proteins
Testicular Neoplasms
Reporter Genes
Colonic Neoplasms
Small Interfering RNA
Spermatozoa
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yang, B., O'Herrin, S. M., Wu, J., Reagan-Shaw, S., Ma, Y., Bhat, K. M. R., ... 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

MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. / Yang, Bing; O'Herrin, Sean M.; Wu, Jianqiang; Reagan-Shaw, Shannon; Ma, Yongsheng; Bhat, Kumar M R; Gravekamp, Claudia; Setaluri, Vijayasaradhi; Peters, Noel; Hoffmann, F. Michael; Peng, Hongzhuang; Ivanov, Alexey V.; Simpson, Andrew J G; Longley, B. Jack.

In: Cancer Research, Vol. 67, No. 20, 15.10.2007, p. 9954-9962.

Research output: Contribution to journalArticle

Yang, B, O'Herrin, SM, Wu, J, Reagan-Shaw, S, Ma, Y, Bhat, KMR, Gravekamp, C, Setaluri, V, Peters, N, Hoffmann, FM, Peng, H, Ivanov, AV, Simpson, AJG & Longley, BJ 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, vol. 67, no. 20, pp. 9954-9962. https://doi.org/10.1158/0008-5472.CAN-07-1478
Yang, Bing ; O'Herrin, Sean M. ; Wu, Jianqiang ; Reagan-Shaw, Shannon ; Ma, Yongsheng ; Bhat, Kumar M R ; Gravekamp, Claudia ; Setaluri, Vijayasaradhi ; Peters, Noel ; Hoffmann, F. Michael ; Peng, Hongzhuang ; Ivanov, Alexey V. ; Simpson, Andrew J G ; Longley, B. Jack. / MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. In: Cancer Research. 2007 ; Vol. 67, No. 20. pp. 9954-9962.
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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.",
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T1 - MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines

AU - Yang, Bing

AU - O'Herrin, Sean M.

AU - Wu, Jianqiang

AU - Reagan-Shaw, Shannon

AU - Ma, Yongsheng

AU - Bhat, Kumar M R

AU - Gravekamp, Claudia

AU - Setaluri, Vijayasaradhi

AU - Peters, Noel

AU - Hoffmann, F. Michael

AU - Peng, Hongzhuang

AU - Ivanov, Alexey V.

AU - Simpson, Andrew J G

AU - Longley, B. Jack

PY - 2007/10/15

Y1 - 2007/10/15

N2 - 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.

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