Developmental Biology - Cell Structure|
What Signals Muscle Cell Differentiation?
Novel genes are responsible for regulating muscle cells...
At York University in Toronto, Canada, scientists have uncovered a unique set of genes in muscle gene expression and differentiation — which could lead to new therapeutic targets preventing muscle cancer spread.
Published in the journal Cell Death & Disease, the study indicates how a dysfunctional relationship between Smad7 and ß-catenin can lead to impaired muscle cell differentiation — a hallmark of some soft tissue cancers such as Rhabdomyosarcoma (RMS). This rare cancer most often affects children and forms in soft, mostly skeletal muscle tissue, although sometimes in hollow organs like the bladder or uterus.
Regulatory proteins Smad7 and ß-catenin cooperatively regulate muscle cell differentiation, growth, and repair. When working in harmony,
their control of signalling pathways of gene expression results in normal skeletal muscle cells.
"What happens in rhabdomyosarcoma cells is that normal muscle cells cannot stop dividing," explains John McDermott, professor, department of Biology at York University, Toronto, who supervised the study and is a contributing author. Although these cells look like muscle cells, in terms of function and phenotype, their inability to stop dividing forms tumors.
"Our idea is that part of the reason why those cells are defective...is that the ß-catenin complex is being degraded...because of an anomaly in the signaling pathway. If we can stabilize the ß-catenin and Smad7 complex...you could potentially encourage them to differentiate and stop proliferating...you'd stop those cells from growing in the tumor."
John C. McDermott PhD, Department of Biology, York University, Toronto, Canada; Muscle Health Research Centre (MHRC); Centre for Research in Biomolecular Interactions (CRBI); and Centre for Research in Mass Spectrometry (CRMS), York University, Toronto, ON, Canada.
Research conducted in York's Muscle Health Research Centre, the first of its kind in Canada, focuses on skeletal muscle. With this new finding, it will also open up new molecular targets for interventions in muscle wasting, leading to strategies for cancer treatments targeting these specific molecules.
By identifying the role of DNA binding proteins, the team also opens possible new regulators of muscle regeneration and avenues for treating the loss of muscle in aging.
"Muscle regeneration is complex and regulated by a variety of transcription factors — essential proteins that help turn genes on or off by binding to specific ones. We believe two such transcription factors, Smad7 and ß-catenin, play a key role in the specific pattern of gene expression required for muscle development and repair."
Soma Tripathi PhD, Department of Biology, York University, Toronto, Canada; Muscle Health Research Centre (MHRC); Centre for Research in Biomolecular Interactions (CRBI); and Centre for Research in Mass Spectrometry (CRMS), York University, Toronto, ON, Canada.
Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-? signaling. Here further characterization of the myogenic function of Smad7 revealed ß-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of ß-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and ß-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and ß-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the ß-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished ß-catenin function, indicating that SID functions as a trans dominant-negative regulator of ß-catenin activity. ß-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-ß-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration.
Soma Tripathi, Tetsuaki Miyake and John C. McDermott.
This work was supported by the Canadian Institutes of Health Research (102688 to J.C.M.). J.C.M. is supported by the McLaughlin Research Chair, York University.
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