Regulation Of SirT1 Activity By Tumor Suppressor ARF

As the most homologic homologue of silent information regulator 2 of yeast, SirT1 gene is extensively expressed in mature tissues, and is rich in early embryo and reproductive cells. It is involved in the regulation of gene transcription, energy metabolism and cell aging.The ARF protein is one of the most important tumor suppressor and it plays widespread and independent role in tumor suppression. This tumor suppressor functions in the p53 and pRb cell cycle regulatory pathways and can effectively activate both pathways to induce cell cycle arrest or cell death. Although much of ARF's tumor suppressor activity is mediated through p53, it also has p53-independent function. ARF can interact with many proteins and increase their post-translational modifications without p53. This might be a general mechanism by which ARF could perform its p53-independent effects on gene expression and tumor suppression.In this study, we proved SirT1 is a novel binding protein of ARF, and the expression level of SirT1 can be down-regulated by ARF. We were able to find the two proteins form a complex and detect their colocalization when SirT1 and ARF are expressed in vivo. And the ubiquitination and sumolation of SirT1 could be dramatically increased as ARF accumulated. Two ARF mutants,1-64 binds to SirT1 while the other one 65-132 does not. This research is only in its infancy. We hope our study may reveal more potential function of ARF-SirT1 interaction and provide theory basis for SirT1 in the regulation of gene transcription, energy metabolism, cell aging and drug susceptibility.