The Zinc Finger-Only Protein Zfp260 Is a Novel Cardiac Regulator and a Nuclear Effector of α1-Adrenergic Signaling

Abstract

α1-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 α1-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 α1-adrenergic stimulation. Interestingly, Zfp260 transcripts are induced by α1-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 α1-adrenergic signaling.

ACKNOWLEDGMENTS

We are grateful to Gérard Goubin for the gift of OZF antibody and for sharing data, Gaétan Thibault for help with radioimmunoassay, André Turgeon for help with blood pressure measurements, Lynda Robitaille and Chantal Lefebvre for excellent technical assistance, Lise Laroche for secretarial help, Annie Vallée for the tissue sections, Jacques Lavigne for DNA sequencing, and Bert Vogelstein for the plasmid and bacteria required for generation of the first recombinant adenovirus. We thank Stéphanie Monnier for bioinformatics and members of the Nemer laboratory for helpful discussions.

S.D. received a fellowship from the Fondation de la Recherche Médicale (France), and M.M. of a Bourse d'Excellence from the Education Ministry of Québec. This study was supported by a grant from the Canadian Institutes of Health Research (MT13056). M.N. holds a Canada Research Chair in Molecular Biology.