title: Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion protein.
abstract: Promyelocytic leukemia zinc finger-retinoic acid receptor a (PLZF-RARalpha), 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 RARalpha/retinoid X receptor alpha (RXRalpha). 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-RARalpha proteins, is primarily responsible for this activity. To further investigate the mechanisms of PLZF-RARalpha 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)-RARalpha, which is expressed in the majority of APLs as a result of t(15;17) translocation. PLZF-RARalpha and PML-RARalpha have essentially the same ligand-binding affinities and can bind in vitro to retinoic acid response elements (RAREs) as homodimers or heterodimers with RXRalpha. PLZF-RARalpha homodimerization and heterodimerization with RXRalpha were primarily mediated by the POZ-domain and RARalpha sequence, respectively. Despite having identical RARalpha sequences, PLZF-RARalpha and PML-RARalpha homodimers recognized with different affinities distinct RAREs. Furthermore, PLZF-RARalpha could heterodimerize in vitro with the wild-type PLZF, suggesting that it may play a role 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-RARalpha and PML-RARalpha may underlie, at least in part, the apparent resistance of APL with t(11;17) to differentiation effects of all-trans-retinoic acid.
authors.affiliation: Laboratory of Molecular Biology, Shanghai Institute of Hematology, Shanghai Second Medical University (SSMU) Peoples Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Dong
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: A
authors.initials: A
authors.lastname: Reid
authors.forename: P
authors.initials: P
authors.lastname: Strutt
authors.forename: F
authors.initials: F
authors.lastname: Guidez
authors.forename: H J
authors.initials: HJ
authors.lastname: Zhong
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Licht
authors.forename: S
authors.initials: S
authors.lastname: Waxman
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Zelent
authors.forename: S J
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015342:DNA Probes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008024:Ligands; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D011487:Protein Conformation; D011817:Rabbits; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D014178:Translocation, Genetic; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D015342:DNA Probes; D004268:DNA-Binding Proteins; D008024:Ligands; D009687:Nuclear Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; C090212:ZBTB6 protein, human