Thrombopoietin-induced conformational change in p53 lies downstream of thep44/p42 mitogen activated protein kinase cascade in the human growth factor-dependent cell line M07e

Thrombopoietin is a cytokine with potent megakaryocytopoietic and thrombopo ietic activities in who. Wild-type p53 is a conformationally flexible, anti -oncogenic transcription factor that plays a principal role in mediating gr owth factor withdrawal-induced apoptosis in factor-dependent hematopoietic cells. We recently reported that Tpo induces a conformational change in and functional inactivation of p53, coincident with its anti-apoptotic effects , in the human factor-dependent cell line M07e. In an effort to identify po tential signaling cascades through which Tpo illicits these effects on p53, we report here that treating M07e cells with MAPK kinase inhibitor PD98059 dramatically suppressed Tpo-induced conformational change in p53 as well a s Tpo-enhanced viability in M07e cells in a p53-dependent manner. Furthermo re, the expression of constitutively active Raf1 in M07e cells induced conf ormational change in p53 independent of Tpo stimulation. Inhibition of the JAK/STAT pathway revealed that JAK/STAT signaling plays an insignificant ro le in conformational modulation of p53 and apoptosis suppression. Inhibitio n of phosphatidylinositol-3 kinase did not have a significant effect on p53 conformation but did have a weak but significant effect on Tpo-enhanced vi ability. Cytokine-induced activation of the MAPK pathway and the subsequent functional neutralization of p53, may be an event by which apoptosis is co mmonly suppressed in hematopoiesis.