Inactivation of zinc finger transcription factors provides a mechanism for a gene regulatory role of nitric oxide.
Nitric oxide (NO) is known to induce Zn(2+) release from the zinc-storing protein metallothionein and to induce Zn(2+) 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, 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) receptor (VDR) and retinoid X receptor (RXR) with 1alpha,25(OH)(2)D(3) 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 (IC(50) 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 1alpha,25(OH)(2)D(3) signaling (IC(50) 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
KD
Research Group Immunobiology, Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, Germany. kroencke@uniduesseldorf.de
Carlberg
C
C
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002117:Calcitriol / Q000037:antagonists & inhibitors / Q000378:metabolism; D017931:DNA Primers; D019281:Dimerization; D009569:Nitric Oxide / Q000502:physiology*; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D016335:Zinc Fingers
D017931:DNA Primers; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D009569:Nitric Oxide; D002117:Calcitriol