AMINO-TERMINAL PROTEIN-PROTEIN INTERACTION MOTIF (POZ-DOMAIN) IS RESPONSIBLE FOR ACTIVITIES OF THE PROMYELOCYTIC LEUKEMIA ZINC-FINGER RETINOIC ACID RECEPTOR-ALPHA FUSION PROTEIN
S. Dong et al., AMINO-TERMINAL PROTEIN-PROTEIN INTERACTION MOTIF (POZ-DOMAIN) IS RESPONSIBLE FOR ACTIVITIES OF THE PROMYELOCYTIC LEUKEMIA ZINC-FINGER RETINOIC ACID RECEPTOR-ALPHA FUSION PROTEIN, Proceedings of the National Academy of Sciences of the United Statesof America, 93(8), 1996, pp. 3624-3629
Promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-
RAR alpha), a fusion receptor generated as a result of a variant t(11;
17) chromosomal translocation that occurs in a small subset of acute p
romyelocytic leukemia (APL) patients, has been shown to display a domi
nant-negative effect against the wild-type RAR alpha/retinoid X recept
or alpha (RXR alpha). We now show that its N-terminal region (called t
he POZ-domain), which mediates protein-protein interaction as well as
specific nuclear localization of the wild-type PLZF and chimeric PLZF-
RAR alpha proteins, is primarily responsible for this activity, To fur
ther investigate the mechanisms of PLZF-RAR alpha action, we have also
studied its ligand-receptor, protein-protein, and protein-DNA interac
tion properties and compared them with those of the promyelocytic leuk
emia gene (PML)-RAR alpha, which is expressed in the majority of APLs
as a result of t(15;17) translocation, PLZF-RAR alpha and PML-RAR alph
a have essentially the same ligand-binding affinities and can bind in
vitro to retinoic acid response elements (RAREs) as homodimers or hete
rodimers with RXR alpha. PLZF-RAR alpha homodimerization and heterodim
erization with RXR alpha were primarily mediated by the POZ-domain and
RAR alpha sequence, respectively, Despite having identical RAR alpha
sequences, PLZF-RAR alpha and PML-RAR alpha homodimers recognized with
different affinities distinct RAREs. Furthermore, PLZF-RAR alpha coul
d 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 hut also the wild-type PLZF and possibly other
POZ-domain-containing regulators. These different protein-protein inte
ractions and the target gene specificities of PLZF-RAR alpha and PML-R
AR alpha may underlie, at least in part, the apparent resistance of AP
L with t(11;17) to differentiation effects of all-trans-retinoic acid.