Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis

Signal transducer and activator of transcription (STAT) proteins perform ke y roles in mediating signaling by cytokines and growth factors, including p latelet-derived growth factor (PDGF). In addition, Src family kinases activ ate STAT signaling and are required for PDGF-induced mitogenesis in normal cells. One STAT family member, Stat3, has been shown to have an essential r ole in cell transformation by the Src oncoprotein. However, the mechanisms by which STAT-signaling pathways contribute to mitogenesis and transformati on are not fully defined. We show here that disruption of Stat3 signaling b y using dominant-negative Stat3 beta protein in NIH 3T3 fibroblasts suppres ses c-Myc expression concomitant with inhibition of v-Src-induced transform ation. Ectopic expression of c-Myc is able to partially reverse this inhibi tion, suggesting that c-Myc is a downstream effector of Stat3 signaling in v-Src transformation. Furthermore, c-myc gene knockout fibroblasts are refr actory to transformation by v-Src, consistent with a requirement for c-Myc protein in v-Src transformation. In normal NIH 3T3 cells, disruption of Sta t3 signaling with dominant-negative Stat3 beta protein inhibits PDGF-induce d mitogenesis in a manner that is reversed by ectopic c-Myc expression. Mor eover, inhibition of Src family kinases with the pharmacologic agent, 5U665 6, blocks Stat3 activation by PDGF. These findings, combined together, deli neate the signaling pathway, PDGF --> Src --> Stat3 --> Myc, that is import ant in normal PDGF-induced mitogenesis and subverted in Src transformation.