Fusion proteins of the retinoic acid-alpha recruit histone deacetylase in promyelocytic leukaemia
| Autor: | Francesco Grignani, Silvia De Matteis, Clara Nervi, Lucia Tomassoni, Vania Gelmetti, Mario Cioce, Mirco Fanelli, Marthin Ruthardt, Fabiana F. Ferrara, Iris Zamir, Christian Seiser, Fausto Grignani, Mitchell A. Lazar, Saverio Minucci, Pier Giuseppe Pelicci |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 1998 |
| Předmět: |
Oncogene Proteins
Fusion Receptors Retinoic Acid PLZF/RAR Tretinoin Hydroxamic Acids Histone Deacetylases Cell Line Leukemia Promyelocytic Acute PML/RAR retinoic acid Nuclear Receptor Co-Repressor 1 Cloning Molecular Enzyme Inhibitors Histone deacetylase 5 Multidisciplinary Binding Sites biology HDAC11 Histone deacetylase 2 HDAC10 Retinoic Acid Receptor alpha Tumor Suppressor Proteins Nuclear Proteins Cell Differentiation Histone acetyltransferase Neoplasm Proteins DNA-Binding Proteins Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors Repressor Proteins Retinoic acid receptor alpha Mutagenesis biology.protein Cancer research Histone deacetylase activity Histone deacetylase Protein Binding Transcription Factors |
| Popis: | The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|