A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins.
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).
Pubmed ID: 10610177
- Zhong S
- Delva L
- Rachez C
- Cenciarelli C
- Gandini D
- Zhang H
- Kalantry S
- Freedman LP
- Pandolfi PP
November 7, 1999
- Agency: NCI NIH HHS, Id: CA-08748
- Agency: NCI NIH HHS, Id: CA71692
- Agency: NCI NIH HHS, Id: CA74031
- CREB-Binding Protein
- Cell Differentiation
- Cell Division
- Cell Line
- Cell Nucleus
- Cell Transformation, Neoplastic
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Leukemia, Promyelocytic, Acute
- Neoplasm Proteins
- Nuclear Proteins
- Oncogene Proteins, Fusion
- Promoter Regions, Genetic
- Protein Binding
- Protein Isoforms
- Receptors, Retinoic Acid
- Retinoid X Receptors
- Transcription Factors
- Thyroid carcinoma, papillary is related to genes TRIM24, TIF1, TIF1A, PTC6 which are autosomal dominant according to the OMIM database.
- Leukemia, acute promyelocytic is related to gene RARA.
- Adenocarcinoma of lung, somatic is related to genes BRAF, NS7 which are autosomal recessive according to the OMIM database.
- Noonan syndrome 7 is related to genes BRAF, NS7.
- LEOPARD syndrome 3 is related to genes BRAF, NS7.
- Cardiofaciocutaneous syndrome is related to genes BRAF, NS7 which are autosomal dominant according to the OMIM database.