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- W2256023856 abstract "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." @default.
- W2256023856 created "2016-06-24" @default.
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- W2256023856 date "2016-01-19" @default.
- W2256023856 modified "2023-10-12" @default.
- W2256023856 title "TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome" @default.
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- W2256023856 doi "https://doi.org/10.1172/jci80937" @default.
- W2256023856 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4731168" @default.
- W2256023856 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26784546" @default.
- W2256023856 hasPublicationYear "2016" @default.
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