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Open Access Highly Accessed Research article

Regulation of GAD65 expression by SMAR1 and p53 upon Streptozotocin treatment

Sandeep Singh2*, Varsheish Raina1, Pavithra Lakshminarsimhan Chavali1, Taronish Dubash1, Sreenath Kadreppa1, Pradeep Parab1 and Samit Chattopadhyay1*

Author Affiliations

1 Samit Chattopadhyay, PhD, Scientist-G, National Centre for Cell Sciences, Pune, 411007, India

2 Sandeep Singh, Assistant Professor, Centre for Human Genetics, School of Health Sciences, Central University of Punjab, Bathinda, 151001, India

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BMC Molecular Biology 2012, 13:28  doi:10.1186/1471-2199-13-28

Published: 14 September 2012

Abstract

Background

GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of β-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription.

Results

The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse β-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment.

Conclusion

We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53.

Keywords:
SMAR1; Diabetes; GAD65; p53; Streptozotocin