TGF- beta / beta 2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome
Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. In this paper, the authors have reported that double-heterozygous Sptbn1 super( +/-) Smad3 super( +/-) mice, which have defective T...
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| Veröffentlicht in: | The Journal of clinical investigation 2016-02, Vol.126 (2), p.527-527 |
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| creator | Chen, Jian Yao, Zhi-Xing Chen, Jiun-Sheng Gi, Young Jin Munoz, Nina M Kundra, Suchin Herlong, H Franklin Jeong, Yun Seong Goltsov, Alexei Ohshiro, Kazufumi Mistry, Nipun A Zhang, Jianping Su, Xiaoping Choufani, Sanaa Mitra, Abhisek Li, Shulin Mishra, Bibhuti White, Jon Rashid, Asif Wang, Alan Yaoqi Javle, Milind Davila, Marta Michaely, Peter Weksberg, Rosanna Hofstetter, Wayne L Finegold, Milton J Shay, Jerry W Machida, Keigo Tsukamoto, Hidekazu Mishra, Lopa |
| description | Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. In this paper, the authors have reported that double-heterozygous Sptbn1 super( +/-) Smad3 super( +/-) mice, which have defective TGF- beta signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. They further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF- beta inducible and facilitates TGF- beta -mediated repression of TERT transcription via interactions with beta 2SP and SMAD3. This regulation was abrogated in TGF- beta -defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, they propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF- beta pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations. |
| doi_str_mv | 10.1172/JCI80937 |
| format | Article |
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In this paper, the authors have reported that double-heterozygous Sptbn1 super( +/-) Smad3 super( +/-) mice, which have defective TGF- beta signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. They further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF- beta inducible and facilitates TGF- beta -mediated repression of TERT transcription via interactions with beta 2SP and SMAD3. This regulation was abrogated in TGF- beta -defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, they propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF- beta pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.</description><identifier>ISSN: 0021-9738</identifier><identifier>DOI: 10.1172/JCI80937</identifier><language>eng</language><ispartof>The Journal of clinical investigation, 2016-02, Vol.126 (2), p.527-527</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27915,27916</link.rule.ids></links><search><creatorcontrib>Chen, Jian</creatorcontrib><creatorcontrib>Yao, Zhi-Xing</creatorcontrib><creatorcontrib>Chen, Jiun-Sheng</creatorcontrib><creatorcontrib>Gi, Young Jin</creatorcontrib><creatorcontrib>Munoz, Nina M</creatorcontrib><creatorcontrib>Kundra, Suchin</creatorcontrib><creatorcontrib>Herlong, H Franklin</creatorcontrib><creatorcontrib>Jeong, Yun Seong</creatorcontrib><creatorcontrib>Goltsov, Alexei</creatorcontrib><creatorcontrib>Ohshiro, Kazufumi</creatorcontrib><creatorcontrib>Mistry, Nipun A</creatorcontrib><creatorcontrib>Zhang, Jianping</creatorcontrib><creatorcontrib>Su, Xiaoping</creatorcontrib><creatorcontrib>Choufani, Sanaa</creatorcontrib><creatorcontrib>Mitra, Abhisek</creatorcontrib><creatorcontrib>Li, Shulin</creatorcontrib><creatorcontrib>Mishra, Bibhuti</creatorcontrib><creatorcontrib>White, Jon</creatorcontrib><creatorcontrib>Rashid, Asif</creatorcontrib><creatorcontrib>Wang, Alan Yaoqi</creatorcontrib><creatorcontrib>Javle, Milind</creatorcontrib><creatorcontrib>Davila, Marta</creatorcontrib><creatorcontrib>Michaely, Peter</creatorcontrib><creatorcontrib>Weksberg, Rosanna</creatorcontrib><creatorcontrib>Hofstetter, Wayne L</creatorcontrib><creatorcontrib>Finegold, Milton J</creatorcontrib><creatorcontrib>Shay, Jerry W</creatorcontrib><creatorcontrib>Machida, Keigo</creatorcontrib><creatorcontrib>Tsukamoto, Hidekazu</creatorcontrib><creatorcontrib>Mishra, Lopa</creatorcontrib><title>TGF- beta / beta 2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome</title><title>The Journal of clinical investigation</title><description>Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. In this paper, the authors have reported that double-heterozygous Sptbn1 super( +/-) Smad3 super( +/-) mice, which have defective TGF- beta signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. They further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF- beta inducible and facilitates TGF- beta -mediated repression of TERT transcription via interactions with beta 2SP and SMAD3. This regulation was abrogated in TGF- beta -defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, they propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF- beta pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.</description><issn>0021-9738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNotjs1OAyEYADloYq0mPgJHL1g-WBb2qBtba5p4qfHYUPjWovsnsDG-vTX1NJfJZAi5AX4HoMXiuV4bXkl9RmacC2CVluaCXKb0wTkUhSpmJG9XS0b3mC1dnCBYGtHlGPpFva2XLOL71NqMnuapGyJN0zhGTCkMPQ09PUyd7WnK2FGHbUt9SEP0GOkDus_vkA_sLaDHo3S0fnofhw6vyHlj24TX_5yT1-Xjtn5im5fVur7fsBHAZOaB70UhjWuEdAJKBaKylnsHEpWqTGXBKkTVCK3Be1l54UupdOMab0tr5ZzcnrpjHL4mTHnXhfR3aXscprQDXRplSqUL-QtzEFyO</recordid><startdate>20160201</startdate><enddate>20160201</enddate><creator>Chen, Jian</creator><creator>Yao, Zhi-Xing</creator><creator>Chen, Jiun-Sheng</creator><creator>Gi, Young Jin</creator><creator>Munoz, Nina M</creator><creator>Kundra, Suchin</creator><creator>Herlong, H Franklin</creator><creator>Jeong, Yun Seong</creator><creator>Goltsov, Alexei</creator><creator>Ohshiro, Kazufumi</creator><creator>Mistry, Nipun A</creator><creator>Zhang, Jianping</creator><creator>Su, Xiaoping</creator><creator>Choufani, Sanaa</creator><creator>Mitra, Abhisek</creator><creator>Li, Shulin</creator><creator>Mishra, Bibhuti</creator><creator>White, Jon</creator><creator>Rashid, Asif</creator><creator>Wang, Alan Yaoqi</creator><creator>Javle, Milind</creator><creator>Davila, Marta</creator><creator>Michaely, Peter</creator><creator>Weksberg, Rosanna</creator><creator>Hofstetter, Wayne L</creator><creator>Finegold, Milton J</creator><creator>Shay, Jerry W</creator><creator>Machida, Keigo</creator><creator>Tsukamoto, Hidekazu</creator><creator>Mishra, Lopa</creator><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20160201</creationdate><title>TGF- beta / beta 2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome</title><author>Chen, Jian ; 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In this paper, the authors have reported that double-heterozygous Sptbn1 super( +/-) Smad3 super( +/-) mice, which have defective TGF- beta signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. They further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF- beta inducible and facilitates TGF- beta -mediated repression of TERT transcription via interactions with beta 2SP and SMAD3. This regulation was abrogated in TGF- beta -defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, they propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF- beta pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.</abstract><doi>10.1172/JCI80937</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| title | TGF- beta / beta 2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome |
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