ABSTRACT
Hereditary cancer syndromes provide powerful insights into dysfunctional signaling pathways that lead to sporadic cancers. Beckwith-Wiedemann syndrome (BWS) is a hereditary human cancer stem cell syndrome currently linked to deregulated imprinting at chromosome 11p15 and uniparental disomy. However, causal molecular defects and genetic models have remained elusive to date in the majority of cases. The non-pleckstrin homology domain ß-spectrin (ß2SP) (the official name for human is Spectrin, beta, nonerythrocytic 1 (SPTBN1), isoform 2; the official name for mouse is Spectrin beta 2 (Spnb2), isoform 2), a scaffolding protein, functions as a potent TGF-ß signaling member adaptor in tumor suppression and development. Yet, the role of the ß2SP in human tumor syndromes remains unclear. Here, we report that ß2SP(+/-) mice are born with many phenotypic characteristics observed in BWS patients, suggesting that ß2SP mutant mice phenocopy BWS, and ß2SP loss could be one of the mechanisms associated with BWS. Our results also suggest that epigenetic silencing of ß2SP is a new potential causal factor in human BWS patients. Furthermore, ß2SP(+/-) mice provide an important animal model for BWS, as well as sporadic cancers associated with it, including lethal gastrointestinal and pancreatic cancer. Thus, these studies could lead to further insight into defects generated by dysfunctional stem cells and identification of new treatment strategies and functional markers for the early detection of these lethal cancers that otherwise cannot be detected at an early stage.
Subject(s)
Beckwith-Wiedemann Syndrome/genetics , Epigenesis, Genetic , Neoplastic Stem Cells/metabolism , Spectrin/genetics , Animals , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Base Sequence , Blotting, Western , DNA Methylation/drug effects , Decitabine , Enzyme Inhibitors/pharmacology , Epigenomics , Gene Expression Profiling , Hep G2 Cells , Heterozygote , Humans , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Mice , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Phenotype , Promoter Regions, Genetic/genetics , Spectrin/metabolism , Tumor Cells, CulturedABSTRACT
Transforming growth factor beta (TGF-beta) signaling has diverse and complex roles in various biological phenomena such as cell growth, differentiation, embryogenesis and morphogenesis. ES cells provide an essential model for understanding the role of TGF-beta signaling in lineage specification and differentiation. Recent studies have suggested significant role of TGF-beta in stem/progenitor cell biology. Here in this review, we focus on the role of the TGF-beta superfamily in neuronal development.
Subject(s)
Neurons/metabolism , Signal Transduction , Stem Cells/metabolism , Transforming Growth Factor beta/metabolism , Animals , Cell Differentiation , Cell Division , Embryonic Development , Humans , Morphogenesis , Neurons/cytology , Receptors, Notch/metabolism , Stem Cells/cytologyABSTRACT
The transforming growth factor-beta (TGF-beta) superfamily comprises nearly 30 growth and differentiation factors that include TGF-betas, activins, inhibins, and bone morphogenetic proteins (BMPs). Multiple members of the TGF-beta superfamily serve key roles in stem cell fate commitment. The various members of the family can exhibit disparate roles in regulating the biology of embryonic stem (ES) cells and tumor suppression. For example, TGF-beta inhibits proliferation of multipotent hematopoietic progenitors, promotes lineage commitment of neural precursors, and suppresses epithelial tumors. BMPs block neural differentiation of mouse and human ES cells, contribute to self-renewal of mouse ES cells, and also suppress tumorigenesis. ES cells and tumors may be exposed to multiple TGF-beta members, and it is likely that the combination of growth factors and cross-talk among the intracellular signaling pathways is what precisely defines stem cell fate commitment. This Connections Map Pathway in the Database of Cell Signaling integrates signaling not only from TGF-beta and BMP but also from the ligands nodal and activin, and describes the role of the signaling pathways activated by these ligands in mammalian development. Much of the evidence for the connections shown comes from studies on mouse and human ES cells or mouse knockouts. This pathway is important for understanding not only stem cell biology, but also the molecular effectors of TGF-beta and BMP signaling that may contribute to cancer suppression or progression and thus are potential targets for therapeutic intervention.
