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Inactivation of zinc finger transcription factors provides a mechanism for a gene regulatory role of nitric oxide

KLAUS-DIETRICH KRÖNCKE^*1 and CARSTEN CARLBERG

^* Research Group Immunobiology and
Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, Germany

¹Correspondence: Forschungsgruppe Immunbiologie 14.80, Heinrich-Heine-Universität Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany. E-mail: kroencke{at}uni-duesseldorf.de

Nitric oxide (NO) is known to induce Zn²⁺ release from the zinc-storing protein metallothionein and to induce Zn²⁺ release within the nuclei and cytoplasm of cells. This suggests that zinc finger proteins may be primary targets of NO-induced stress. In this study, the specific interaction of the heterodimeric complex of two zinc finger transcription factors, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) receptor (VDR) and retinoid X receptor (RXR) with 1,25(OH)₂D₃ response elements (VDREs), was used as a model system. NO was applied to this system via the NO donors SNOC and MAMA/NO and caused a dose-dependent inhibition of VDR-RXR-VDRE complex formation (IC₅₀ values 0.5–0.8 mM). Ligand-bound or preformed complexes displayed less sensitivity to NO-induced stress. These in vitro effects of NO were found to be reversible. Functional assays in transiently transfected cells indicated that NO can also act in vivo as a repressor of 1,25(OH)₂D₃ signaling (IC₅₀ value of the slow NO donor DETA/NO, 0.5 mM). These findings suggest that NO has a modulatory role on transcription factors depending on their sensitivity to NO-induced stress, thus providing a mechanism for a gene regulatory function of NO.—Kröncke, K. D., Carlberg, C. Inactivation of zinc finger transcription factors provides a mechanism for a gene regulatory role of nitric oxide.

Key Words: protein–DNA interaction • transcriptional regulation/1 • 25(OH)₂D₃ receptor 1,25(OH)₂D₃ signaling

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