Activation of GSNOR transcription by NF-κB negatively regulates NGF-induced PC12 differentiation

S-nitrosoglutathione reductase (GSNOR) is the key enzyme controlling the intracellular levels of S-nitrosoglutathione and S-nitrosothiols. GSNOR has been implicated in many biological processes, such as the cardiovascular and respiratory systems. However, the role of GSNOR, the sole brain alcohol dehydrogenase, in the nervous systems is still largely a mystery. Here we report that GSNOR was induced during the PC12 neuronal differentiation. Luciferase assays indicated that the region of -88bp to -73bp of the GSNOR promoter encodes an essential responsive sequence to nerve growth factor (NGF). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays revealed NF-kappa B binds to this essential sequence, which demonstrates that GSNOR can be activated by NF-kappa B in response to NGF. Blocking either the neurotrophic tyrosine kinase receptor type 1 (TrkA receptor) for NGF or the downstream MEK1/2 pathway inhibited the increase of GSNOR. In contrast to usual neurogenic signals in response to NGF, GSNOR negatively regulated neurite growth; overexpression of GSNOR significantly decreased the percent of differentiated cells, and knockdown of GSNOR promoted the differentiation. To our knowledge, this is the first time the transcriptional mechanism of GSNOR in neuronal differentiation has been explored. We have defined a novel role of GSNOR in neurite development and provide molecular insights into the control of neurite growth.