Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2
Sarkar, Fazlul H.
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CitationWang, Zhiwei, Hiroyuki Inuzuka, Jiateng Zhong, Pengda Liu, Fazlul H. Sarkar, Yi Sun, and Wenyi Wei. 2012. “Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2.” Oncotarget 3 (11): 1294-1300.
AbstractThe Skp2 (S-phase kinase associated protein 2) oncoprotein is often highly expressed in various types of human cancers. However, the mechanistic basis of its oncogenic function, as well as the upstream regulatory pathway(s) that control Skp2 activities remains not fully understood. Recently, we reported that p300 acetylates Skp2 at two conserved lysine residues K68 and K71 within its NLS (Nuclear localization signal). This modification leads to increased Skp2 stability and cytoplasmic translocation, thus contributing to elevated Skp2 oncogenic potential. Moreover, we found that the SIRT3 tumor suppressor serves as the physiological deacetylase that antagonizes p300-mediated Skp2 acetylation. Furthermore, we showed that Skp2 governs E-cadherin ubiquitination and degradation in the cytosol. Consistent with this, we observed an inverse correlation between Skp2 and E-cadherin expression in clinical breast tumor samples. Therefore, our work elucidates a novel acetylation-dependent regulatory mechanism for Skp2 oncogenic functions.
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