Promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF- RARα), a fusion receptor generated as a result of a variant t(11;17) chromosomal translocation that occurs in a small subset of acute promyelocytic leukemia (APL) patients, has been shown to display a dominant- negative effect against the wild-type RARα/retinoid X receptor α (RXRα). We now show that its N-terminal region (called the POZ-domain), which mediates protein-protein interaction as well as specific nuclear localization of the wild-type PLZF and chimeric PLZF-RARα proteins, is primarily responsible fur this activity. To further investigate the mechanisms of PLZF- RARα action, we have also studied its ligand-receptor, protein-protein, and protein-DNA interaction properties and compared them with those of the promyelocytic leukemia gene (PML)-RARα, which is expressed in the majority of APLs as a result of t(15;17) translocation. PLZF-RARα and PML-RARα have essentially the same ligand-binding affinities and can bind in vitro to retinoic acid response elements (RAREs) as homodimers or heterodimers with RXRα. PLZF-RARα homodimerization and heterodimerization with RXRα were primarily mediated by the POZ-domain and RARα sequence, respectively. Despite having identical RARα sequences, PLZF-RARα and PML-RARα homodimers recognized with different affinities distinct RAREs. Furthermore, PLZF-RARα could heterodimerize in vitro with the wild-type PLZF, suggesting that it may play a rule in leukemogenesis by antagonizing actions of not only the retinoid receptors but also the wild-type PLZF and possibly other POZ- domain-containing regulators. These different protein-protein interactions and the target gene specificities of PLZF-RARα and PML-RARα may underlie, at least in part, the apparent resistance of APL with t(11;17) to differentiation effects of all-trans-retinoic acid.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Apr 16 1996|
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