Our research interest concerns the basic regulatory mechanisms involved in cellular differentiation. This work is primarily undertaken using cardiac, skeletal and smooth muscle cells and neurons as model systems and is aimed at understanding the role of transcription factors in orchestrating tissue-specific gene expression and differentiation.
The genesis of this work was in identifying DNA binding proteins that are involved in transcriptional regulation during muscle development. Subsequent work explored the mechanisms by which these factors regulate cellular gene expression and differentiation. A main focus of our work has been the molecular cloning and characterization of a family of transcription factors (four genes, labelled MEF2A-D) that regulate the expression of many cardiac, smooth and skeletal muscle specific genes via the myocyte enhancer factor 2 (MEF2) cis- element. Based on their structural similarity, these genes belong to the MADS superfamily of DNA binding proteins that are involved in cell fate specification in many organisms ranging from yeasts to humans. Since the identification of the MEF2 gene family, further studies have been undertaken to assess the biological role of these genes during cardiac and skeletal muscle differentiation as well as in a variety of post-natal contexts such as cardiac disease (hypertrophy) and muscle regeneration.
It is well known that various intracellular signalling pathways potently regulate cell differentiation by targeting nuclear transcription factors. Moreover, muscle differentiation is extremely sensitive to the action of various growth factors. Therefore, our aim is to delineate the growth factor-activated signalling pathways that specifically converge on and modulate key transcriptional regulators such as MEF2 proteins during myogenesis. We are currently dissecting the effects of kinase mediated phosphorylation of MEF2 protein in order to fully understand how it serves as a nuclear sensor of growth factor -activated signalling pathways. In this regard we have reported a key role of the p38 MAP kinase pathway in targeting MEF2 in the somites during embryogenesis. Included in this post translational analysis of MEF2 function is the identification of MEF2 interacting proteins using state of the art tools in Mass Spectrometry. Studies are also ongoing to determine the contribution of other transcriptional regulators such as the Fra2 subunit of the AP-1 complex and the Smad7 protein to the myogenic program in cardiac and skeletal muscle cells. This work is supported by the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC) of Canada and the Heart and Stroke Foundation of Canada (HSF).
Belozerov VE, Ratkovic S, McNeill H, Hilliker AJ, McDermott JC. In Vivo Interaction Proteomics Reveal a Novel p38 Mitogen-Activated Protein Kinase/Rack1 Pathway Regulating Proteostasis in Drosophila Muscle. Mol Cell Biol. 2014 Feb;34 (3):474-84.
Alli NS, Yang EC, Miyake T, Aziz A, Collins-Hooper H, Patel K, McDermott JC. Signal-dependent fra-2 regulation in skeletal muscle reserve and satellite cells. Cell Death Dis. 2013 Jun 27;4:e692. doi: 10.1038/cddis.2013.221.
Dionyssiou MG, Salma J, Bevzyuk M, Wales S, L LZ, McDermott JC Krüppel-like factor 6 (KLF6) promotes cell proliferation in skeletal myoblasts in response to TGFβ/Smad3 signaling. Skelet Muscle. 2013 Apr 2;3(1):7.
Dionyssiou MG, Nowacki NB, Hashemi S, Zhao J, Kerr A, Tsushima RG, McDermott JC. Cross-talk between glycogen synthase kinase 3β (GSK3β) and p38MAPK regulates myocyte enhancer factor 2 (MEF2) activity in skeletal and cardiac muscle. J Mol Cell Cardiol. 2013 Jan;54:35-44. Epub 2012 Nov 5.
Belozerov VE, Lin ZY, Gingras AC, McDermott JC, Michael Siu KW. High-Resolution Protein Interaction Map of the Drosophila melanogaster p38 Mitogen-Activated Protein Kinases Reveals Limited Functional Redundancy. Mol Cell Biol. 2012 Sep;32(18):3695-706. Epub 2012 Jul 16.
Salma J, McDermott JC. Suppression of a MEF2-KLF6 Survival Pathway by PKA Signaling Promotes Apoptosis in Embryonic Hippocampal Neurons. J.Neurosci.2012 Feb 22;32(8):2790-803.
Pagiatakis C, Gordon JW, Ehyai S, McDermott JC A novel RhoA/ROCK- CPI-17 -MEF2C signaling pathway regulates vascular smooth muscle cell gene expression. J Biol Chem. 2012 Mar 9;287(11):8361-70. Epub 2012 Jan 23