Abstract
Identification of AP-1 target genes in apoptosis and differentiation has proved elusive. Secretogranin II (SgII) is a protein widely distributed in nervous and endocrine tissues, and abundant in neuroendocrine granules. We addressed whether SgII is regulated by AP-1, and if SgII is involved in neuronal differentiation or the cellular response to nitrosative stress. Nitric oxide (NO) upregulated sgII mRNA dependent on a cyclic AMP response element (CRE) in the sgII promoter, and NO stimulated SgII protein secretion in neuroblastoma cells. Upregulation of sgII mRNA, sgII CRE-driven gene expression and SgII protein synthesis/export were attenuated in cells transformed with dominant-negative c-Jun (TAM67), which became sensitized to NO-induced apoptosis and failed to undergo nerve growth factor-dependent neuronal differentiation. Stable transformation of TAM67 cells with sgII restored neuronal differentiation and resistance to NO. RNAi knockdown of sgII in cells expressing functional c-Jun abolished neuronal differentiation and rendered the cells sensitive to NO-induced apoptosis. Therefore, SgII represents a key AP-1-regulated protein that counteracts NO toxicity and mediates neuronal differentiation of neuroblastoma cells.
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Abbreviations
- CgA:
-
chromogranin A
- CgB:
-
chromogranin B
- CRE:
-
cyclic AMP response element
- DETA-NO:
-
diethylenetriamine nitric oxide adduct
- FSK:
-
forskolin
- LDH:
-
lactate dehydrogenase
- NCAM140:
-
neural cell adhesion molecule 140
- NGF:
-
nerve growth factor
- NO:
-
nitric oxide
- SgII:
-
secretogranin II
- SgV:
-
secretogranin V
- SN:
-
secretoneurin
- TRE:
-
TPA (12-O-tetradecanoylphorbol-13-acetate) response element
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Acknowledgements
We thank Zhiwei Feng for much advice and many discussions, and Saravanakumar Dhakshinamoorthy for comments on the manuscript. AGP is an adjunct staff member of The Department of Surgery, National University of Singapore. This study was supported by the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.
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Li, L., Hung, A. & Porter, A. Secretogranin II: a key AP-1-regulated protein that mediates neuronal differentiation and protection from nitric oxide-induced apoptosis of neuroblastoma cells. Cell Death Differ 15, 879–888 (2008). https://doi.org/10.1038/cdd.2008.8
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DOI: https://doi.org/10.1038/cdd.2008.8
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