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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2007 |
|---|---|
| Erschienen: |
2007 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Cancer research - 67(2007), 20 vom: 15. Okt., Seite 9954-62 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Bing [VerfasserIn] |
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| Anmerkungen: |
Date Completed 12.12.2007 Date Revised 18.03.2022 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM17444978X |
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| 100 | 1 | |a Yang, Bing |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines |
| 264 | 1 | |c 2007 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
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| 500 | |a Date Completed 12.12.2007 | ||
| 500 | |a Date Revised 18.03.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antigens, Neoplasm |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Repressor Proteins |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
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| 700 | 1 | |a O'Herrin, Sean M |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jianqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Reagan-Shaw, Shannon |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yongsheng |e verfasserin |4 aut | |
| 700 | 1 | |a Bhat, Kumar M R |e verfasserin |4 aut | |
| 700 | 1 | |a Gravekamp, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Setaluri, Vijayasaradhi |e verfasserin |4 aut | |
| 700 | 1 | |a Peters, Noel |e verfasserin |4 aut | |
| 700 | 1 | |a Hoffmann, F Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Hongzhuang |e verfasserin |4 aut | |
| 700 | 1 | |a Ivanov, Alexey V |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Andrew J G |e verfasserin |4 aut | |
| 700 | 1 | |a Longley, B Jack |e verfasserin |4 aut | |
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