Activation of the TGF-β/Smad signaling pathway in oncogenic transformation by v-Rel

v-rel, encoded by the avian reticuloendotheliosis virus, is an acutely transforming member of the Rel/NF-κB family of transcription factors. Transformation by v-Rel is mediated by the aberrant expression of genes that are normally regulated by Rel/NF-κB. Here, we demonstrate activation of the TGF-β/Smad signaling pathway in Rel transformation. RNA and protein levels of key TGF-β and Smad family members (TGF-β2, -β3, TGF-β type II receptor, and Smad3) are upregulated in v-Rel transformed cells with little to no change in c-Rel-expressing cells. Treatment of v-Rel transformed lymphoid cells with kinase inhibitors of the TGF-β receptor dramatically reduces soft agar colony formation whereas addition of TGF-β2 further promotes transformation. Moreover, Smad3 but not Smad2, is selectively activated as the downstream mediator of TGF-β signaling. Blocking Smad3 expression or activity inhibits the oncogenic potential of v-Rel. Overall, TGF-β/Smad signaling is activated at multiple levels and is required for the transforming ability of v-Rel.