Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes
| Autor: | Satoru Usami, Koichiro Kuwahara, Yuko Yamada, Chinatsu Yamada, Masao Murakami, Toshio Nishikimi, Leo Hata, Kazuwa Nakao, Masataka Fujiwara, Yasuaki Nakagawa, Kazuhiro Nakao, Takeya Minami, Kenji Ueshima, Shinji Yasuno, Yoshihiro Kuwabara, Hideyuki Kinoshita |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Two-hybrid screening Repressor Mice Transgenic Biology MECP2 Mice Transcription (biology) Chlorocebus aethiops Gene Order Animals Humans RNA Messenger Molecular Biology Transcription factor Zinc finger Gene knockdown Base Sequence Ventricular Remodeling Gene Expression Regulation Developmental DNA-binding domain Middle Aged Rats Mice Inbred C57BL Repressor Proteins HEK293 Cells COS Cells Cancer research Female Cardiology and Cardiovascular Medicine Protein Binding |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 50:972-981 |
| ISSN: | 0022-2828 |
| Popis: | Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down-regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc-finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF-target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction. |
| Databáze: | OpenAIRE |
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