PLZF-RAR-ALPHA FUSION PROTEINS GENERATED FROM THE VARIANT T(11-17)(Q23-Q21) TRANSLOCATION IN ACUTE PROMYELOCYTIC LEUKEMIA INHIBIT LIGAND-DEPENDENT TRANSACTIVATION OF WILD-TYPE RETINOIC ACID RECEPTORS
PLZF-RAR-ALPHA FUSION PROTEINS GENERATED FROM THE VARIANT T(11-17)(Q23-Q21) TRANSLOCATION IN ACUTE PROMYELOCYTIC LEUKEMIA INHIBIT LIGAND-DEPENDENT TRANSACTIVATION OF WILD-TYPE RETINOIC ACID RECEPTORS
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DOI：
10.1073/pnas.91.3.1178
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发表时间：
1994-02-01
影响因子：
11.1
通讯作者：
CHOMIENNE, C
中科院分区：
文献类型：
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作者：
CHEN, Z;GUIDEZ, F;CHOMIENNE, C
最近，我们描述了急性早幼粒细胞白血病 (APL) 中的一种复发性变体易位 t(11;17)(q23;q21)，该易位将编码锌指蛋白的基因 PLZF 与编码视黄酸受体 α (RARα) 的基因 RARA 并置。我们现在已经克隆了编码 PLZF-RARalpha 嵌合蛋白的 cDNA，并研究了它们的反式激活活性。在瞬时表达测定中，PLZF(A)-RARα 和 PLZF(B)-RARα 融合蛋白（如 APL 中众所周知的 t(15;17) 易位产生的 PML-RARα 蛋白）在视黄酸存在下拮抗内源性和转染的野生型 RARα。共转染测定表明，即使使用非常低的 PLZF-RARα 表达质粒浓度，也能显着抑制 RARα 反式激活活性。当 PLZF-RARα 融合蛋白与表达 RARα 和类视黄醇 X 受体 α (RXRα) 的载体共转染时，观察到“显性负”效应。在视黄酸敏感的骨髓细胞中观察到的这些异常反式激活特性强烈暗示 PLZF-RARα 融合蛋白与 APL 的分子发病机制有关。
Recently, we described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor alpha (RARalpha). We have now cloned cDNAs encoding PLZF-RARalpha chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RARalpha and PLZF(B)-RARalpha fusion proteins like the PML-RARalpha protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RARalpha in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RARalpha transactivation activity was obtained even with a very low PLZF-RARalpha-expressing plasmid concentration. A ''dominant negative'' effect was observed when PLZF-RARalpha fusion proteins were cotransfected with vectors expressing RARalpha and retinoid X receptor alpha (RXRalpha). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RARalpha fusion proteins in the molecular pathogenesis of APL.