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.