The cytoskeleton-associated PDZ-LIM protein, ALP, acts on serum response factor activity to regulate muscle differentiation.
In this report, an antisense RNA strategy has allowed us to show that disruption of ALP expression affects the expression of the muscle transcription factors myogenin and MyoD, resulting in the inhibition of muscle differentiation. Introduction of a MyoD expression construct into ALP-antisense cells is sufficient to restore the capacity of the cells to differentiate, illustrating that ALP function occurs upstream of MyoD. It is known that MyoD is under the control of serum response factor (SRF), a transcriptional regulator whose activity is modulated by actin dynamics. A dramatic reduction of actin filament bundles is observed in ALP-antisense cells and treatment of these cells with the actin-stabilizing drug jasplakinolide stimulates SRF activity and restores the capacity of the cells to differentiate. Furthermore, we show that modulation of ALP expression influences SRF activity, the level of its coactivator, MAL, and muscle differentiation. Collectively, these results suggest a critical role of ALP on muscle differentiation, likely via cytoskeletal regulation of SRF.
Pomiès
Pascal
P
Centre National de la Recherche Scientifique Unité Mixte de Recherche 5237, Centre de Recherches de Biochimie Macromoléculaire, 34293 Montpellier, France. pascal.pomies@crbm.cnrs.fr
Pashmforoush
Mohammad
M
Vegezzi
Cristina
C
Chien
Kenneth R
KR
Auffray
Charles
C
Beckerle
Mary C
MC
D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D060588:LIM Domain Proteins; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D024510:Muscle Development / Q000235:genetics / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism*; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics; D026362:Serum Response Factor / Q000378:metabolism*; D014162:Transfection
D000199:Actins; D017931:DNA Primers; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051787:Myogenic Regulatory Factor 5; C484642:Pdlim3 protein, mouse; D016372:RNA, Antisense; D026362:Serum Response Factor; D000185:Actinin