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Molecular mechanisms of regulation of proliferation, differentiation and death of hematopietic cells by CREB/ATF family proteins : an application to molecular-targeted therapy of hematopoietic malignancies

CREB/ATF家族蛋白调控造血细胞增殖、分化和死亡的分子机制：在造血系统恶性肿瘤分子靶向治疗中的应用

基本信息

批准号：
14571008
负责人：
SAEKI Kumiko
金额：
$ 2.24万
依托单位：
International Medical Center of Japan (Research Institute)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

We evaluated the involvement of cAMP-response element (CRE)-dependent transcriptions in all-trans retinoic acid (ATRA)-induced myeloid differentiation using human monoblastic U937 cells. ATRA treatment caused an increment in CRE-dependent transcription activity and induced a wide variety of differentiation phenotypes including the functional and morphological maturation. Indeed, ATRA treatment induced an expression of CCAAT/enhancer-binding protein β (C/EBPβ), a CRE-dependent transcription factor important for monocytic differentiation, and the inhibition of CRE enhancer activity by the expression of a dominant negative cAMP-response element-binding protein (dominant negative CREB, dn-CREB) abolished the induction of C/EBPβ. Functional maturation such as an enhancement in cell adhesion and respiratory burst activity were dramatically suppressed by the expression of dn-CREB. In accordance with these, the differentiation-dependent induction of adhesion molecule (CD11b), the phagocyte oxidase for the respiratory burst and the transcription factor PU.1 responsible for the phagocyte oxidase induction was all eradicated by dn-CREB. Quite surprisingly, morphological maturation including nuclear convolution and cytoplasmic vacuolar formation were augmented by dn-CREB. Under the same condition, the differentiation-associated cell growth arrest was not affected by the expression of dn-CREB. Our results clearly indicate that CRE-driven transcription plays at least three distinct roles during the single process of myeloid differentiation : it stimulates functional maturation but suppresses morphological maturation while giving no effects on cell growth arrest.

我们评估了cAMP反应元件（CRE）依赖的translavin参与全反式维甲酸（ATRA）诱导的人单核细胞U937髓系分化。ATRA处理引起CRE-dependent转录活性的增加，并诱导各种分化表型，包括功能和形态成熟。事实上，ATRA处理诱导了CCAAT/增强子结合蛋白β（C/EBPβ）的表达，这是一种对单核细胞分化很重要的CRE依赖性转录因子，通过表达显性负性cAMP反应元件结合蛋白（显性负性CREB，dn-CREB）抑制CRE增强子活性，消除了C/EBPβ的诱导。dn-CREB的表达显著抑制了细胞粘附和呼吸爆发活性的增强等功能成熟。根据这些，分化依赖的诱导粘附分子（CD 11b），吞噬细胞氧化酶的呼吸爆发和转录因子PU.1负责吞噬细胞氧化酶的诱导都根除dn-CREB。非常令人惊讶的是，形态成熟，包括核卷曲和细胞质空泡的形成增强dn-CREB。在相同条件下，dn-CREB的表达对分化相关的细胞生长停滞没有影响。我们的结果清楚地表明，CRE驱动的转录在骨髓分化的单个过程中至少发挥三种不同的作用：它刺激功能成熟，但抑制形态成熟，同时对细胞生长停滞没有影响。