| Autor: |
Dong, Shuo, Qiu, Jihui, Stenoien, David L, Brinkley, William R, Mancini, Michael A, Tweardy, David J |
| Předmět: |
|
| Zdroj: |
Oncogene; 2/13/2003, Vol. 22 Issue 6, p858, 11p |
| Abstrakt: |
Nuclear mitotic apparatus protein-retinoic acid receptor α (NuMA-RARα) is the fourth of five fusion proteins identified in acute promyelocytic leukemia (APL) patients. The molecular basis for its oncogenic activity has not been delineated. In gel-shift assays, NuMA-RARα bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRα. The binding profile of NuMA-RARα to a panel of RAREs was very similar to PML-RARα and PLZF-RARα. In transient transfection assays using HepG2 cells, NuMA-RARα inhibited wild-type RARα transcriptional activity, while it augmented STAT3 transcriptional activity. In GST-pull down experiments, NuMA-RARα formed a complex with the corepressor SMRT, was released from the NuMA-RARα/SMRT complexes by all-trans retinoic acid (ATRA) at 10-7–10-6 M and became associated with the coactivator TRAM-1 at 10-8 M ATRA. Studies comparing NuMA-RARα with NuMA-RARα(ΔCC) demonstrated that the dimerization or α-helical coiled-coil domain of NuMA was required for homodimer formation, transcriptional repression of wild-type RARα, transcriptional activation of STAT3, and stability of the NuMA-RARα/SMRT complex. Confocal fluorescent microscopy of HeLa cells was performed following transient expression of cyan fluorescent protein (CFP)-tagged proteins and incubation of cells with or without ATRA. Within the nucleus, CFP-NuMA-RARα exhibited a speckled pattern identical to that observed in cells transfected with CFP-NuMA. Furthermore, CFP-NuMA-RARα colocalized with yellow fluorescent protein-tagged (YFP)-NuMA. In contrast, CFP-NuMA-RARα(ΔCC) exhibited a diffuse granular pattern within the nucleus, similar to RARα. These results indicate that the dimerization domain of NuMA-RARα is critical for each of the known oncogenic activities of NuMA fusion proteins as well as its... [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
