SMAR1 和 p53 对链脲佐菌素处理后 GAD65 表达的调节。

Regulation of GAD65 expression by SMAR1 and p53 upon Streptozotocin treatment.

机构信息

Centre for Human Genetics, School of Health Sciences, Central University of Punjab, Bathinda 151001, India.

出版信息

BMC Mol Biol. 2012 Sep 14;13:28. doi: 10.1186/1471-2199-13-28.

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.

背景

谷氨酸脱羧酶 65（Glutamic acid decarboxylase 65 KDa isoform）是参与 1 型糖尿病诱导的最重要的自身抗原之一。尽管它是β-胰岛的最初损伤标志物之一，但调控 GAD65 表达的机制仍知之甚少。由于 GAD65 的调控对于胰岛素分泌细胞的正常功能至关重要，我们研究了应激诱导的 GAD65 转录调控。

结果

本研究表明 SMAR1 在转录水平上调控 GAD65 的表达。使用新型蛋白-DNA 下拉测定法，我们发现 SMAR1 结合非常特异性地与 GAD65 启动子结合，但不与其他同工酶 GAD67 结合。我们表明链脲佐菌素（STZ）介导的 DNA 损伤导致 SMAR1 和 p53 的表达上调，导致两种细胞系以及小鼠β胰岛中 GAD65 的水平升高。SMAR1 和 p53 在 STZ 处理时协同作用以上调 GAD65 的表达。