Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-α fusion protein

Shuo Dong, Jun Zhu, Alan Reid, Philip Strutt, Fabien Guidez, Hao Jie Zhong, Zhen Yi Wang, Jonathan Licht, Samuel Waxman, Christine Chomienne, Zhu Chen, Arthur Zelent, Sai Juan Chen

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)3624-3629
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number8
DOIs
StatePublished - Apr 16 1996

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