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

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Abstract
Transforming growth factor-β1 (TGF-β) is a growth factor that has multiple functions including potent inhibition of cell growth. TGF-β 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 β (gag–RXRβ) fusion protein was found to antagonize TGF-β-induced growth inhibition of mink lung epithelial cells and the fusion between gag and RXRβ is essential for resistance to the growth inhibition. Like gag–RXRβ, the oncogenic PLZF–RARα fusion protein also antagonizes TGF-β-induced growth inhibition, and the fusion between PLZF and RARα is essential for resistance to TGF-β. Moreover, TGF-β and retinoic acid (RA) cooperatively induce growth inhibition as well as transcription of the p15ink4b gene, while PLZF–RARα represses TGF-β-induced expression of the p15ink4b gene. Together, these results suggest that the TGF-β and RA pathways cooperate to inhibit cell growth and that PLZF–RARα -mediated resistance to TGF-β may facilitate the development of the PLZF–RARα-induced leukemia.