Acute promyelocytic leukemia (APL) is generally associated with a chromosomal translocation that fuses a nuclear protein of unknown function with the DNA- and ligand-binding domains of retinoid acid receptor alpha (RAR alpha). Treatment with retinoid acid induces clinical remission in APL. This project proposes a test of the transcriptional competence of the PML-RAR fusion protein using native receptor proteins purified from cells infected with vaccinia virus vectors. Binding site preferences for the PML-RAR homodimer and heterodimer with RXR will be determined and compared to the binding preference of native RXR-RAR heterodimers. Ligand-induced conformational changes of PML-RAR will be determined and compared with similar changes in RAR. Finally, an in vitro transcription assay will be used to examine the functionality of PML-RAR by itself and in conjunction with RXR.
| Betz, J L; Chang, M; Washburn, T M et al. (2002) Phenotypic analysis of Paf1/RNA polymerase II complex mutations reveals connections to cell cycle regulation, protein synthesis, and lipid and nucleic acid metabolism. Mol Genet Genomics 268:272-85 |
| Stunnenberg, H G; Garcia-Jimenez, C; Betz, J L (1999) Leukemia: the sophisticated subversion of hematopoiesis by nuclear receptor oncoproteins. Biochim Biophys Acta 1423:F15-33 |
