Fusion proteins of retinoid receptors antagonize TGF-β-induced growth inhibition of lung epithelial cells

Transforming growth factor-beta1 (TGF-beta) is a growth factor that has multiple functions including potent inhibition of cell growth. TGF-beta signals by binding to its cell surface serine/threonine kinase receptors, which in turn phosphorylate downstream signal transducers, Smad2 and Smad3. Phosphorylated Smad2 and Smad3, together with Smad4, enter the nucleus and associate with various transcription factors. This complex of transcription factors regulates transcription of a diverse group of genes, leading to growth arrest at G1 phase. Through a functional expression cloning approach, a gag-retinoid X receptor beta (gag-RXRbeta) fusion protein was found to antagonize TGF-beta-induced growth inhibition of mink lung epithelial cells and the fusion between gag and RXRbeta is essential for resistance to the growth inhibition. Like gag-RXRbeta, the oncogenic PLZF-RARalpha fusion protein also antagonizes TGF-beta-induced growth inhibition, and the fusion between PLZF and RARalpha is essential for resistance to TGF-beta. Moreover, TGF-beta and retinoic acid (RA) cooperatively induce growth inhibition as well as transcription of the p15(inkb) gene, while PLZF-RARalpha represses TGF-beta-induced expression of the p15(ink4b) gene. Together, these results suggest that the TGF-beta and RA pathways cooperate to inhibit cell growth and that PLZF-RARalpha -mediated resistance to TGF-beta may facilitate the development of the PLZF-RARalpha-induced leukemia.