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Function and Regulation of the Human NAD+-dependent Protein Deacetylase SIRT2

出版	University of California, San Francisco, 2005
ISBN	05424613749780542461378
URL	http://books.google.com.hk/books?id=7LYn6_KN-08C&hl=&source=gbs_api

註釋We identify human sirtuin type 2 (SIRT2) as a predominantly cytoplasmic protein colocalizing with the microtubule network. SIRT2 deacetylates lysine-40 of alpha-tubulin and knockdown of SIRT2 by sIRNA results in alpha-tubulin hyperacetylation. alpha-Tubulin deacetylation by SIRT2 results in cytoplasmic sequestration of the transcription factor MIZ-1 by regulating its interaction with the microtubule network. During interphase, SIRT2 shuttles between the nucleus and cytoplasm, and maintains a predominantly cytoplasmic localization via active nuclear export in a Crm1-dependent manner. We have identified a functional Leptomycin B-sensitive nuclear export signal sequence within the amino-terminal extension of SIRT2. During mitotic entry, SIRT2 accumulates in the nucleus prior to nuclear envelope breakdown and during mitosis is enriched on microtubule-derived structures, beginning with the centrosome during prophase, the mitotic spindle during metaphase, and the midbody during cytokinesis. Cells overexpressing either wild-type or catalytically inactive SIRT2 have a greater susceptibility for cytokinesis defects in which cells become multinucleated. During mitosis, we find that SIRT2 is phosphorylated on serine-368, which can be regulated by the opposing activities of the Cdk1 kinase and the CDC14A and CDC14B phosphatases. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on the presence of serine-368.