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

Oncogene volume 22, pages 198–210 (2003)Cite this article

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.

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Acknowledgements

This work is in part supported by a Howard Temin Award (1K01CA78592) and a Burroughs Wellcome Career Award for Biomedical Research (#1676). XH is a recipient of a Howard Temin Award and a Burroughs Wellcome Career Award for Biomedical Research. We thank the following scientists for their generosity in sharing various reagents: Dr S Minucci at European Institute of Oncology for pSG5-RARα, pSG5-PML-RARα, and pcDNA3-PLZF-RARα constructs, Dr D Chakravarti at the University of Pennsylvania for pCMX-RARα and pCMX-RXRα constructs, Dr X Liu at the University of Colorado at Boulder for the probe of p15INK4b, and Dr G Nolan at Stanford University for the E-NX ecotropic packaging cell line. We thank Drs Craig Thompson, Gary Koretzky, Steve Reiner, Mitch Lazar, and Debu Chakravarti for reading the manuscript.

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  1. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104-6160, PA, USA

    Ping La, Trish A Morgan, Stephen M Sykes, Hua Mao, Robert W Schnepp, Clark D Petersen & Xianxin Hua

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La, P., Morgan, T., Sykes, S. et al. Fusion proteins of retinoid receptors antagonize TGF-β-induced growth inhibition of lung epithelial cells. Oncogene 22, 198–210 (2003). https://doi.org/10.1038/sj.onc.1206100

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