DNp73α protects myogenic cells from apoptosis

The P73 gene is transcribed from two promoters, P1 and P2, that direct the expression of multiple transactivation competent (TA) and dominant negative (DN) isoforms. TAp73 transcription

factors mediate cell cycle arrest and/or apoptosis in response to DNA damage and are involved in developmental processes. P73 mRNA levels increase and the P1p73 promoter is upregulated

during myogenic differentiation of C2C12 skeletal muscle satellite cells. The DNp73 proteins act as trans-repressors of p53- and p73-dependent transcription, and possess both antiapoptotic

and pro-proliferative potential. Here, we show that DNp73α is expressed in proliferating C2C12 myoblasts, rapidly accumulates in differentiating myocytes and remains elevated in C2C12

myotubes. By combining transactivation assays and chromatin immunoprecipitation analysis, we could show that the upregulation of the P2p73 promoter during myogenic differentiation is

mediated by the coordinated recruitment and activity of MyoD and p53/p73. Abrogation of DNp73 expression by specific siRNA led to a strong potentiation of the spontaneous apoptosis of C2C12

myoblasts induced to differentiate. Finally, unlike TAp73 that contributes to DNA damage-induced apoptosis of myotubes, endogenous DNp73 mediates the relative resistance of differentiated

myotubes to DNA damage. Altogether, our findings identify DNp73α as an important target in designing strategies aimed at the potentiation of the regenerative potential of skeletal satellite

cells.

This work was supported by grants from AIRC and MIUR-FIRB (to ML and GB), European Community (LSHC-CT-2004-503576 to ML and GB), Telethon (To GB and ML) and MIUR-Cofin and Schering-Plough

(to ML). LB and PM were supported by a fellowship from the Fondazione A. Cesalpino. FM was supported by a fellowship from FIRC. AD was supported by a fellowship from EMBO.

Fondazione A Cesalpino and Department of Internal Medicine, University of Rome ‘La Sapienza’, Rome, Italy

Rome Oncogenomic Center, Regina Elena Cancer Institute, Rome, Italy

Department of Experimental Oncology, Regina Elena Cancer Center, Rome, Italy

Department of Dermatology, University of Tor Vergata, Rome, Italy

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