Altered nuclear cofactor switching in retinoic-resistant variants of the PML-RARα oncoprotein of acute promyelocytic leukemia
| Autor: | Mindy Farris, Jacob Statnekov, Zara Manuelyan, Astrid Lague, Christopher S. Francklyn |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Acute promyelocytic leukemia
Oncogene Proteins Fusion Receptors Retinoic Acid Molecular Sequence Data Retinoic acid Antineoplastic Agents Fluorescence Polarization Tretinoin Chemistry Techniques Synthetic Biology medicine.disease_cause Biochemistry Article Translocation Genetic Structure-Activity Relationship chemistry.chemical_compound Leukemia Promyelocytic Acute Structural Biology Coactivator medicine Humans Myeloid Cells Amino Acid Sequence neoplasms Molecular Biology Cell Nucleus Mutation Circular Dichroism Retinoic Acid Receptor alpha Cell Differentiation medicine.disease Retinol-Binding Proteins chemistry Nuclear receptor Drug Resistance Neoplasm Retinoic acid receptor alpha Proteolysis Cancer research Corepressor medicine.drug |
| Zdroj: | Proteins: Structure, Function, and Bioinformatics. 80:1095-1109 |
| ISSN: | 0887-3585 |
| DOI: | 10.1002/prot.24010 |
| Popis: | Acute Promyelocytic Leukemia (APL) results from a reciprocal translocation that fuses the gene for the PML tumor suppressor to that encoding the retinoic acid receptor alpha (RARα). The resulting PML-RARα oncogene product interferes with multiple regulatory pathways associated with myeloid differentiation, including normal PML and RARα functions. The standard treatment for APL includes anthracycline-based chemotherapeutic agents plus the RARα agonist all-trans retinoic acid (ATRA). Relapse, which is often accompanied by ATRA resistance, occurs in an appreciable frequency of treated patients. One potential mechanism suggested by model experiments featuring the selection of ATRA resistant APL cell lines involves ATRA resistant versions of the PML-RARα oncogene, where the relevant mutations localize to the RARα ligand-binding domain (LBD). Such mutations may act by compromising agonist binding, but other mechanisms are possible. Here, we studied the molecular consequence of ATRA resistance by use of circular dichroism, protease resistance, and fluorescence anisotropy assays employing peptides derived from the NCOR nuclear co-repressor and the ACTR nuclear co-activator. The consequences of the mutations on global structure and co-factor interaction functions were assessed quantitatively, providing insights into the basis of agonist resistance. Attenuated co-factor switching and increased protease resistance represent features of the LBDs of ATRA-resistant PML-RARα, and these properties may be recapitulated in the full-length oncoproteins. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text