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EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1.

Pradhan A.K., Kuila N., Singh S., Chakraborty S.

EVI1 (Ecotropic Viral Integration site I), which was originally identified as a site of viral integration in murine myeloid tumors, encodes a complex protein required for embryogenesis. The gene is known to express inappropriately in many types of human myeloid leukemias and solid tumors. Forced expression of EVI1 in murine hematopoietic precursor cells lead to abnormal differentiation and increased proliferation. EVI1 encodes two sets of zinc finger domains due to which it behaves as a transcriptional factor. However, except a few, the targets of EVI1 are not well understood and hence also the mechanism by which it initiates oncogenesis is not very clear. In this report, we show that SIRT1, a histone deacetylase is a direct target of EVI1. In vivo chromatin immunoprecipitation assay revealed that EVI1 binds to the promoter region of SIRT1 approximately 1kb upstream of the transcription start site. The functionality of the site was deduced by luciferase assay which showed that EVI1 significantly increases the SIRT1 promoter activity. SIRT1 was also found to be up regulated in cell lines and in chronic myeloid leukemia patient samples where EVI1 was detected. Over expression of SIRT1 in cells shows that it interacts with EVI1 and this interaction lead to the deacetylation of the protein. Upon deacetylation the stability of EVI1 was found to be affected which was negatively regulated by nicotinamide (NAM). Our results thus identify an EVI1-SIRT1 axis in the regulation of EVI1 activity suggesting a possible role of SIRT1 in EVI1 positive neoplasms.

Biochim. Biophys. Acta 1809:269-275(2011) [PubMed] [Europe PMC]

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