Distinct roles of mitogen activated protein kinases in the regulation of skeletal muscle satellite cell proliferation and differentiation
Abstract
During embryogenesis, pluripotent cells undergo conversion into highly specialized cell types, which comprise the many diverse tissues and organs found in the adult organism. This conversion is tightly regulated by the presence or absence of environmental signals in the form of peptide growth factors. In skeletal muscle, fibroblast growth factors (FGFs) regulate the growth and differentiation of myoblasts in culture and in vivo. Removal of FGF from primary myoblasts and permanent cell lines in culture results in irreversible cell cycle withdrawal, expression of muscle specific genes, and fusion into multinucleated myotubes. I have focused my research on the elucidation of FGF-dependent intracellular signaling events that mediate proliferation and differentiation of skeletal muscle satellite cells with emphasis on signal transduction via (MAPKs). In order to determine the role of MAPKs in myogenesis I have modulated the activation of MAPK signaling cascades using multiple independent approaches: (1) ectopic expression of either dominant negative or constitutively activated mutants of upstream signal transducers, (2) treatment with pharmacological inhibitors specific for the inhibition of defined MKKs, and (3) ectopic expression MAPK phosphatases (negative regulators of MAPK activity). I found that activation of both the MKK1/2-ERK1/2 and the MKK3p38α/β MAPK signaling modules is necessary for myoblast proliferation. Unexpectedly, activation of neither ERK1/2 nor p38α/β is required to repress myogenesis. However, overexpression of MKP-1, but not MKP-3, is sufficient to induce terminal differentiation, suggesting a potential role for MAPK(s) other than ERK1/2 in the direct regulation myogenesis. Interestingly, inhibition of p38α/β activity blocks differentiation of MM14 cells, indicating that activation of p38α/β by growth factor receptors other than FGFR1 is required for differentiation. Together, these results suggest that activation of distinct subsets of MAPKs is required to mediate discrete biological activities within one cell type. Furthermore, individual MAPKs are involved in multiple biological responses and activation of those MAPKs is mediated by different upstream activators.
Degree
Ph.D.
Advisors
Olwin, Purdue University.
Subject Area
Cellular biology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.