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A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARα and T18 oncoproteins

Nature Genetics volume 23, pages 287–295 (1999)Cite this article

Abstract

PML and Tif1a are fused to RARA and Braf, respectively, resulting in the production of PML-RARα and Tif1α-B-Raf (T18) oncoproteins. Here we show that PML, Tif1α and RXRα/RARα function together in a transcription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXRα/RARα. PML interacts with Tif1α and CBP. In Pml–/– cells, the RA-dependent induction of genes such as RARB2 and the ability of Tif1α and CBP to act as transcriptional coactivators on RA are impaired. We show that both PML and Tif1α are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RARα, disrupts the RA-dependent activity of this complex in a dominant-negative manner resulting in a growth advantage. Our data define a new pathway for the control of cell growth and tumorigenesis, and provide a new model for the pathogenesis of acute promyelocytic leukaemia (APL).

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Figure 1: PML is a coactivator of the RARα/RXRα transcription complex.
Figure 2: Endogenous PML binds selectively to liganded GST-RARα.
Figure 3: Loss of Pml impairs RA-dependent transcription.
Figure 4: PML interacts with Tif1α and CBP in vivo.
Figure 5: Tif1α is a growth suppressor.
Figure 6: T18 delocalizes Tif1α from the nucleus to the cytoplasm.
Figure 7: T18 is a dominant-negative inhibitor of the RA-dependent nuclear complex.
Figure 8: A schematic representation of the role of TGS-RANC and a new model for APL pathogenesis.

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Acknowledgements

We thank M. Barna, C. Chomienne, T. Delohery, G.P. Dotto, M. Fagioli, P.S. Freemont, F. Grosveld, L. Longo, L. Luzzatto, T. Miki, P.G. Pelicci, V. Richon, P. Sassone-Corsi, K. Scotto, A. Simeone and E. Singh for help, materials and advice. Partially supported by the "Ligue Nationale contre le Cancer" of France (L.D.) and the American-Italian Cancer Foundation (D.G.). P.P.P. is a scholar of the Leukemia Society of America. Supported by the NCI (CA-08748) and NIH (CA71692 and CA74031 to P.P.P.) and the Human Frontiers Science Program (to C.R. and L.P.F.).

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Authors and Affiliations

  1. Department of Human Genetics, Sloan-Kettering Division, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, New York, New York, USA

    Sue Zhong, Laurent Delva, Cristina Cenciarelli, Domenica Gandini, Hui Zhang, Sundeep Kalantry & Pier Paolo Pandolfi

  2. Sloan-Kettering Division, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, New York, New York, USA

    Christophe Rachez & Leonard P. Freedman

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Zhong, S., Delva, L., Rachez, C. et al. A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARα and T18 oncoproteins. Nat Genet 23, 287–295 (1999). https://doi.org/10.1038/15463

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