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MBC in Press, published online ahead of print January 26, 2003
Mol. Biol. Cell 10.1091/mbc.E02-03-0156

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Submitted on ,
Revised on November 13, 2002
Accepted on December 26, 2002

IGF-I-INDUCED DIFFERENTIATION OF L6 MYOGENIC CELLS REQUIRES THE ACTIVITY OF cAMP-PHOSPHODIESTERASE

Vania De Arcangelis1, Dario Coletti1, Marco Conti2, Michel Lagarde3, Mario Molinaro1, Sergio Adamo1, Georges Nemoz3, and Fabio Naro1*

1 Dip. di Istologia ed Embriologia Medica, Universita di Roma La Sapienza, 00161 Roma, Italia
2 Division of Reproductive Biology, Stanford University School of Medicine, Stanford, CA
3 INSERM U352, Lab. de Biochimie et Pharmacologie, INSA de Lyon, 69621, Villeurbanne France

* Corresponding author. E-mail address: fabio.naro{at}uniroma1.it.

Inhibition of type 4 cAMP-specific phosphodiesterase (PDE4) activity in L6-C5 and L6-E9 abolished myogenic differentiation induced by low-serum medium and IGF-I. L6-C5 cells cultured in low-serum medium displayed a PDE4 activity higher than cells cultured in serum-free medium, a condition not sufficient to induce differentiation. In the presence of serum, PDE4D3, the major isoform natively expressed in L6-C5 cells, translocated to a Triton-insoluble fraction, which increased the PDE specific activity of the fraction, and exhibited a Mr shift typical of phosphorylation of this isoform. Furthermore, serum promoted the localization of PDE4D3 to a vesicular subcellular compartment. In L6-C5 cells, IGF-I is a stronger inducer of myogenic differentiation in the presence than in absence of serum. Its ability to trigger differentiation in the absence of serum was restored by overexpressing wild-type PDE4D3, but not a phosphorylation insensitive mutant. This finding was confirmed in single cells overexpressing a GFP-PDE4D3 fusion protein by assessing nuclear accumulation of myogenin in both L6-C5 and L6-E9. Overexpression of other PDE isoforms was less efficient, confirming that PDE4D3 is the physiologically relevant phosphodiesterase isoform in the control of myogenesis. These results show that down-regulation of cAMP signaling through cAMP-phosphodiesterase stimulation is a prerequisite for induction of myogenesis.




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F. Naro, V. De Arcangelis, C. Sette, C. Ambrosio, H. Komati, M. Molinaro, S. Adamo, and G. Nemoz
A Bimodal Modulation of the cAMP Pathway Is Involved in the Control of Myogenic Differentiation in L6 Cells
J. Biol. Chem., December 5, 2003; 278(49): 49308 - 49315.
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