Debrus Sophie, Rahbani Loulwa, Marttila Minna, Delorme Bruno, Paradis Pierre, Nemer Mona
Unité de Recherche en Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal QC H2W 1R7, Canada.
Mol Cell Biol. 2005 Oct;25(19):8669-82. doi: 10.1128/MCB.25.19.8669-8682.2005.
alpha1-Adrenergic receptors mediate several biological effects of catecholamines, including the regulation of myocyte growth and contractility and transcriptional regulation of the atrial natriuretic factor (ANF) gene whose promoter contains an alpha1-adrenergic response element. The nuclear pathways and effectors that link receptor activation to genetic changes remain poorly understood. Here, we describe the isolation by the yeast one-hybrid system of a cardiac cDNA encoding a novel nuclear zinc finger protein, Zfp260, belonging to the Krüppel family of transcriptional regulators. Zfp260 is highly expressed in the embryonic heart but is downregulated during postnatal development. Functional studies indicate that Zfp260 is a transcriptional activator of ANF and a cofactor for GATA-4, a key cardiac regulator. Knockdown of Zfp260 in cardiac cells decreases endogenous ANF gene expression and abrogates its response to alpha1-adrenergic stimulation. Interestingly, Zfp260 transcripts are induced by alpha1-adrenergic agonists and are elevated in genetic models of hypertension and cardiac hypertrophy. The data identify Zfp260 as a novel transcriptional regulator in normal and pathological heart development and a nuclear effector of alpha1-adrenergic signaling.
α1 - 肾上腺素能受体介导儿茶酚胺的多种生物学效应，包括调节心肌细胞生长和收缩力以及心房利钠因子（ANF）基因的转录调控，该基因启动子含有一个α1 - 肾上腺素能反应元件。将受体激活与基因变化联系起来的核途径和效应器仍知之甚少。在此，我们描述了通过酵母单杂交系统分离出一个心脏cDNA，其编码一种新型核锌指蛋白Zfp260，属于转录调节因子的Krüppel家族。Zfp260在胚胎心脏中高度表达，但在出生后发育过程中下调。功能研究表明，Zfp260是ANF的转录激活因子以及关键心脏调节因子GATA - 4的辅因子。在心脏细胞中敲低Zfp260会降低内源性ANF基因表达并消除其对α1 - 肾上腺素能刺激的反应。有趣的是，Zfp260转录本由α1 - 肾上腺素能激动剂诱导，并且在高血压和心脏肥大的遗传模型中升高。这些数据确定Zfp260是正常和病理性心脏发育中的新型转录调节因子以及α1 - 肾上腺素能信号传导的核效应器。
