How ever, our results inhibitor expert are in agreement with these data, p38 inhibition being inhibitory on U0126 mediated tran scriptional mechanism of p21WAF1 and myogenic tran scription factors expression induced by both TPA and U0126, but is not effective on p21WAF1 expression induced by TPA. As a consequence of p38 inhibition, the levels of the hypo phosphorylated/active Inhibitors,Modulators,Libraries form of pRb in SB203580 treated cells are affected only after prolonged treatments with U0126. Conversely, Inhibitors,Modulators,Libraries neither the pRb phosphorylation status nor p21WAF1 accumulation by TPA are impaired by the p38 inhibitor. It is noteworthy that the ERK/p38 ratio is predictive of growth status in a number of tumor cells, which suggests that, on the basis of our previous investigation, U0126 mediated ERK down regulation and the sustained increase in phos pho active p38 favours persistent growth suppression.

Myogenic transcription factors and muscle specific genes in embryonal and alveolar rhabdomyosarcoma Both the MEK ERK inhibitor and TPA induce myogenic specific gene expression, with MHC accumulation in U0126 treated cells Inhibitors,Modulators,Libraries occurring earlier than in TPA treated cells. Early myogenin accumulation Inhibitors,Modulators,Libraries followed by MyoD shows that the myogenic program is rapidly rescued in ERK depleted cells. Cyclin D1 might also be responsible for the delay in the activation of myogenic transcription factors in TPA treated cells. by contrast, cyclin D1 is down regulated by U0126 alone or together with TPA, leading to a rapid start of the myogenic program.

Remarkably, myogenin and MyoD expression, strongly induced by U0126 in both the presence and absence of TPA, are down regulated by the p38 inhibitor, thereby paralleling the pattern observed in p21WAF1 expression. In view of these results, we hypothe size that MyoD, as previously shown in normal myogene sis, and even myogenin might transactivate p21WAF1 expression Inhibitors,Modulators,Libraries in MEK inhibitor treated cells. Indeed, U0126 mediated p21WAF1 expression requires myogenin and MyoD, as demonstrated by its drastic inhibition in myogenin and MyoD siRNA experiments. However, MyoD or myogenin forced expression in RD cells, while inducing an ectopic p21WAF1 promoter, does not induce an increase in Ku-0059436 the p21WAF1 level. The discrepancy between the inability of forced myogenin and MyoD expression to induce p21WAF1 and the ability of these two transcription factors to transactivate an ectopic promoter, in transfected RD cells, suggests that inhibitory pathways responsible for p21WAF1 repression operate at the level of the p21WAF1 endogenous promoter. It is noteworthy that the authors of another study did not detect p21WAF1 promoter transactivation by ectopic MyoD in RD cells.