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Nucleic Acids Research Advance Access published online on August 15, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm594
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Protein/DNA arrays identify nitric oxide-regulated cis-element and trans-factor activities some of which govern neuroblastoma cell viability

Saravanakumar Dhakshinamoorthy1, Shiva Ranjani Sridharan1, Lei Li1, Poh Yong Ng1, Linda M. Boxer2 and Alan G. Porter1,*

1Cell Death and Human Diseases Group, Division of Genomics and Genetics, Institute of Molecular & Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Republic of Singapore and 2Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

*To whom correspondence should be addressed. Tel: +65 6586 9675; Fax: +65 6779 1117; Email: mcbagp{at}imcb.a-star.edu.sg Correspondence may also be addressed to Saravanakumar Dhakshinamoorthy. Tel: +91 80 2852 1314; Fax: +91 80 2852 6285; Email: saravana_d{at}aurigene.com

Received May 28, 2007. Revised July 17, 2007. Accepted July 18, 2007.

Toxic nitric oxide (NO) levels can regulate gene expression. Using a novel protein/DNA array, we show that toxic NO levels regulate the binding of trans-factors to various cis-elements in neuroblastoma cells, including CRE and those recognized by the transcription factors AP1, AP2, Brn-3a, EGR, E2F1 and SP1. Functionality of some of the cis-elements was confirmed by electro mobility shift and reporter assays. Interestingly, CREB, AP-1, Brn-3a, EGR and E2F1 can control mammalian cell viability. NO induced the anti-apoptotic Bcl-2 protein and its mRNA prior to the onset of death of 30–60% of the cells. Promoter analysis of the bcl-2 gene confirmed the involvement of a CRE in NO-dependent bcl-2 transcription. Neuroblastoma cells over-expressing bcl-2 became much more resistant to NO-induced apoptosis; conversely, Bcl-2 knockdown cells were rendered markedly more sensitive to NO. Together these results suggest that Bcl-2 counteracts NO-induced apoptosis in a fraction of the cell population. Thus, NO stimulates the binding of many trans-factors to their cognate cis-elements, some of which can regulate cell viability through transcriptional activation of target genes. Our results emphasize that a DNA/protein array approach can reveal novel, global transcription factor activities stimulated by cell death-regulating molecules.

Present address: Saravanakumar Dhakshinamoorthy, Cell & Assay Biology Group, Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Electronic City Phase II, Hosur Road, Bangalore 560100, India


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