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doi: 10.1242/10.1242/jcs.00037

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PKC-mediated ERK, JNK and p38 activation regulates the myogenic program in human rhabdomyosarcoma cells

Annunziata Mauro^*,1, Carmela Ciccarelli^*,1, Paola De Cesaris¹, Arianna Scoglio², Marina Bouché², Mario Molinaro², Angelo Aquino³ and Bianca Maria Zani^1,

¹ Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito II, 67100 L'Aquila, Italy
² Department of Histology and Embryology, University of Rome `La Sapienza', Via Scarpa 14, 00161 Rome, Italy
³ Department of Neuroscience, Section of Pharmacology and Medical Oncology, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy

Author for correspondence (e-mail: zani{at}univaq.it)

Accepted 28 June 2002

We have previously suggested that PKC has a role in 12-O-Tetradecanoylphorbol-13-acetate (TPA)-mediated growth arrest and myogenic differentiation in human embryonal rhabdomyosarcoma cells (RD).

Here, by monitoring the signalling pathways triggered by TPA, we demonstrate that PKC mediates these effects by inducing transient activation of c-Jun N-terminal protein kinases (JNKs) and sustained activation of both p38 kinase and extracellular signal-regulated kinases (ERKs) (all referred to as MAPKs). Activation of MAPKs following ectopic expression of constitutively active PKC, but not its dominant-negative form, is also demonstrated.

We investigated the selective contribution of MAPKs to growth arrest and myogenic differentiation by monitoring the activation of MAPK pathways, as well as by dissecting MAPK pathways using MEK1/2 inhibitor (UO126), p38 inhibitor (SB203580) and JNK and p38 agonist (anisomycin) treatments. Growth-arresting signals are triggered either by transient and sustained JNK activation (by TPA and anisomycin, respectively) or by preventing both ERK and JNK activation (UO126) and are maintained, rather than induced, by p38. We therefore suggest a key role for JNK in controlling ERK-mediated mitogenic activity. Notably, sarcomeric myosin expression is induced by both TPA and UO126 but is abrogated by the p38 inhibitor. This finding indicates a pivotal role for p38 in controlling the myogenic program. Anisomycin persistently activates p38 and JNKs but prevents myosin expression induced by TPA. In accordance with this negative role, reactivation of JNKs by anisomycin, in UO126-pre-treated cells, also prevents myosin expression. This indicates that, unlike the transient JNK activation that occurs in the TPA-mediated myogenic process, long-lasting JNK activation supports the growth-arrest state but antagonises p38-mediated myosin expression. Lastly, our results with the MEK inhibitor suggest a key role of the ERK pathway in regulating myogenic-related morphology in differentiated RD cells.

Key words: PKC, MAPKs, RD

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