Abstract
ObjectivesDISHEVELLED, EGL‐10, PLECKSTRIN (DEP) domain‐containing 1B (DEPDC1B) promotes dismantling of focal adhesions and coordinates detachment events during cell cycle progression. DEPDC1B is overexpressed in several cancers with expression inversely correlated with patient survival. Here, we analysed the role of DEPDC1B in the regulation of murine and human skeletal myogenesis.Materials and methodsExpression dynamics of DEPDC1B were examined in murine and human myoblasts and rhabdomyosarcoma cells in vitro by RT‐qPCR and/or immunolabelling. DEPDC1B function was mainly tested via siRNA‐mediated gene knockdown.Results DEPDC1B was expressed in proliferating murine and human myoblasts, with expression then decreasing markedly during myogenic differentiation. SiRNA‐mediated knockdown of DEPDC1B reduced myoblast proliferation and induced entry into myogenic differentiation, with deregulation of key cell cycle regulators (cyclins, CDK, CDKi). DEPDC1B and β‐catenin co‐knockdown was unable to rescue proliferation in myoblasts, suggesting that DEPDC1B functions independently of canonical WNT signalling during myogenesis. DEPDC1B can also suppress RHOA activity in some cell types, but DEPDC1B and RHOA co‐knockdown actually had an additive effect by both further reducing proliferation and enhancing myogenic differentiation. DEPDC1B was expressed in human Rh30 rhabdomyosarcoma cells, where DEPDC1B or RHOA knockdown promoted myogenic differentiation, but without influencing proliferation.ConclusionDEPDC1B plays a central role in myoblasts by driving proliferation and preventing precocious myogenic differentiation during skeletal myogenesis in both mouse and human.
Highlights
DISHEVELLED, EGL-10, PLECKSTRIN (DEP) domain-containing 1B (DEPDC1B) and its paralog DEPDC1A are cell cycle–regulating proteins.[1]
DEPDC1B is expressed in proliferating mouse and human myoblasts, but levels rapidly decrease during differentiation, in agreement with DEPDC1B being almost undetectable in human skeletal muscle.[5]
DEPDC1B was present in the nucleus in both proliferating murine myoblasts and differentiated multinucleated myotubes, indicating that while DEPDC1B expression is actively repressed during differentiation, the protein could remain functional in newly formed myotubes
Summary
DISHEVELLED, EGL-10, PLECKSTRIN (DEP) domain-containing 1B (DEPDC1B) and its paralog DEPDC1A are cell cycle–regulating proteins.[1]. The DEP domain is a globular region discovered in DISHEVELLED, EGL-10 and PLECKSTRIN and plays a role in mediating membrane localization,[2] and DEPDC1B is usually membrane-associated, being highly expressed during G2/M phase of the cell cycle.[1,3] The RHO-GAP domain is involved in RHO GTPase signalling (eg RAC, CDC42 and RHO) that regulates cell motility, growth, differentiation, cytoskeleton reorganization and cell cycle progression.[4] Membrane association via the DEP domain enables DEPDC1B to interact with G protein-coupled receptors, as well as membrane phospholipids necessary for Wnt signalling. DEPDC1B plays a central role in driving proliferation and preventing differentiation during skeletal myogenesis
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