| Autor: |
Chen J, Yao ZX, Chen JS, Gi YJ, Muñoz NM, Kundra S, Herlong HF, Jeong YS, Goltsov A, Ohshiro K, Mistry NA, Zhang J, Su X, Choufani S, Mitra A, Li S, Mishra B, White J, Rashid A, Wang AY, Javle M, Davila M, Michaely P, Weksberg R, Hofstetter WL, Finegold MJ, Shay JW, Machida K, Tsukamoto H, Mishra L |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of clinical investigation [J Clin Invest] 2016 Feb; Vol. 126 (2), pp. 527-42. Date of Electronic Publication: 2016 Jan 19. |
| DOI: |
10.1172/JCI80937 |
| Abstrakt: |
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. Epigenetic silencing of β2-spectrin (β2SP, encoded by SPTBN1), a SMAD adaptor for TGF-β signaling, is causally associated with BWS; however, a role of TGF-β deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-β signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-β-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-β inducible and facilitates TGF-β-mediated repression of TERT transcription via interactions with β2SP and SMAD3. This regulation was abrogated in TGF-β-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, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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