Nature Genetics
23, 287 - 295 (1999)
doi:10.1038/15463
A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RAR and T18 oncoproteinsSue Zhong1, Laurent Delva1, Christophe Rachez2, Cristina Cenciarelli1, Domenica Gandini1, Hui Zhang1, Sundeep Kalantry1, Leonard P. Freedman2
& Pier Paolo Pandolfi11
Department of Human Genetics, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York, USA. 2
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
Correspondence should be addressed to Pier Paolo Pandolfi p-pandolfi@ski.mskcc.org
PML and Tif1a are fused to RARA and Braf, respectively, resulting in the production of PML-RAR and Tif1-B-Raf (T18) oncoproteins. Here we show that PML, Tif1 and RXR/RAR function together in a transcription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXR/RAR. PML interacts with Tif1 and CBP. In Pml−/− cells, the RA-dependent induction of genes such as RARB2 and the ability of Tif1 and CBP to act as transcriptional coactivators on RA are impaired. We show that both PML and Tif1 are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RAR, 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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