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A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18
1Department 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.
Abstract:
PML and Tif1a are fused to RARA and Braf, respectively, resulting in the production of PML-RARalpha and Tif1alpha-B-Raf (T18) oncoproteins. Here we show that PML, Tif1alpha and RXRalpha/RARalpha function together in a transcription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXRalpha/RARalpha. PML interacts with Tif1alpha and CBP. In Pml-/- cells, the RA-dependent induction of genes such as RARB2 and the ability of Tif1alpha and CBP to act as transcriptional coactivators on RA are impaired. We show that both PML and Tif1alpha are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RARalpha, 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).
Insights
Promyelocytic leukemia (PML) and Tif1alpha proteins form a transcription complex with retinoic acid (RA) receptors, regulating cell growth. Aberrant fusion proteins like PML-RARalpha disrupt this complex, contributing to acute promyelocytic leukemia (APL) pathogenesis.
Area of Science:
- Molecular Biology
- Cellular Biology
- Oncology
Background:
- The fusion of PML to RARA and Tif1a to Braf generates PML-RARalpha and Tif1alpha-B-Raf (T18) oncoproteins.
- Retinoic acid (RA) signaling is crucial in cellular differentiation and growth control.
Purpose of the Study:
- To elucidate the role of PML and Tif1alpha in RA-dependent transcriptional regulation.
- To investigate the mechanism by which PML-RARalpha and T18 oncoproteins contribute to tumorigenesis.
Main Methods:
- Co-immunoprecipitation assays to study protein interactions.
- Gene expression analysis (e.g., RARB2 induction) in wild-type and Pml-/- cells.
- Functional assays assessing transcriptional coactivator activity and cell growth inhibition.
Main Results:
- PML, Tif1alpha, and RXRalpha/RARalpha form a retinoic acid-dependent transcription complex.
- PML functions as a ligand-dependent coactivator for RXRalpha/RARalpha and interacts with Tif1alpha and CBP.
- RA-dependent gene induction and coactivator function of Tif1alpha and CBP are impaired in Pml-/- cells.
- PML and Tif1alpha act as growth suppressors, mediating RA's inhibitory effects on cell growth.
- The T18 oncoprotein disrupts the complex in a dominant-negative manner, promoting cell growth.
Conclusions:
- PML and Tif1alpha are essential components of an RA-dependent transcription complex that controls cell growth.
- The disruption of this complex by oncoproteins like PML-RARalpha and T18 provides a new model for APL pathogenesis and tumorigenesis.
- This study defines a novel pathway regulating cell growth and tumor development.