The estrogen-responsive B box protein is a novel regulator of the retinoid signal
The estrogen-responsive B box protein is a novel regulator of the retinoid signal
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DOI：
10.1074/jbc.m600879200
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发表时间：
2006-06-30
影响因子：
4.8
通讯作者：
Marshall, Glenn M.
中科院分区：
文献类型：
--
作者：
Cheung, Belamy B.;Bell, Jessica;Marshall, Glenn M.
维甲酸（RA）在体外诱导许多人类癌细胞的生长停滞、细胞死亡和分化，并且已经进入用于治疗几种人类癌症类型的常规临床用途。癌细胞逃避类维生素A诱导作用的一种机制是通过抑制视黄酸受体β（RAR β）基因转录。RA反应元件β（β RARE）是类维生素A诱导的RAR β转录所需的基本DNA序列。在这里，我们表明，雌激素反应B盒蛋白（EBBP），环B盒卷曲螺旋蛋白家族的成员，是一种β稀有结合蛋白。RA治疗后EBBP经历丝氨酸/苏氨酸磷酸化和增强的蛋白质稳定性。在RA治疗后，我们还观察到在早幼粒细胞白血病核小体处与早幼粒细胞白血病蛋白聚集的核EBBP水平增加。EBBP增强了RA敏感和耐药癌细胞中的RA响应性RAR β转录，这些癌细胞对组蛋白脱乙酰酶抑制剂和去甲基化剂都具有抗性。EBBP特异性小干扰RNA降低基础和RA诱导的RAR β表达。EBBP通过其卷曲螺旋结构域增加β RARE反式激活功能。综上所述，我们的工作表明EBBP可能在类维生素A抗癌信号中起关键作用。
Retinoic acid (RA) induces growth arrest, cell death, and differentiation in many human cancer cells in vitro and has entered routine clinical use for the treatment of several human cancer types. One mechanism by which cancer cells evade retinoid-induced effects is through repression of retinoic acid receptor beta (RAR beta) gene transcription. The RA response element beta (beta RARE) is the essential DNA sequence required for retinoid-induced RAR beta transcription. Here we show that the estrogen-responsive B box protein (EBBP), a member of the RING-B box-coiled-coil protein family, is a beta RARE-binding protein. EBBP undergoes serine threonine phosphorylation and enhanced protein stability after RA treatment. Following RA treatment, we also observed increased nuclear EBBP levels in aggregates with the promyelocytic leukemia protein at promyelocytic leukemia nuclear bodies. EBBP enhanced RA-responsive RAR beta transcription in RA-sensitive and -resistant cancer cells, which were resistant to both a histone deacetylase inhibitor and a demethylating agent. EBBP-specific small interfering RNA reduced basal and RA-induced RAR beta expression. EBBP increased beta RARE-transactivating function through its coiled-coil domain. Taken together, our work suggests that EBBP may have a pivotal role in the retinoid anti-cancer signal.