1. A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARα and T18 oncoproteins.
- Author
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Zhong, Sue, Delva, Laurent, Rachez, Christophe, Cenciarelli, Cristina, Gandini, Domenica, Zhang, Hui, Kalantry, Sundeep, Freedman, Leonard P., and Pandolfi, Pier Paolo
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TRANSCRIPTION factors ,TRETINOIN ,CARCINOGENESIS - 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). [ABSTRACT FROM AUTHOR]- Published
- 1999
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