Disease relevance of SIRT2

• SIRT2 is located at 19q13.2, a region known to be frequently deleted in human gliomas [1].
• Since it is however severely reduced in a large number of human brain tumor cell lines, the absence of SIRT2, a potential tumor suppressor, could play a key role in the regulation of the cell-cycle within a multistep pathway that leads to full cellular transformation and, finally, the development of cellular malignancy [2].

High impact information on SIRT2

• Here, we report that a human ortholog of Sir2p, sirtuin type 2 (SIRT2), is a predominantly cytoplasmic protein that colocalizes with microtubules [3].
• SIRT2 deacetylates lysine-40 of alpha-tubulin both in vitro and in vivo [3].
• CDC14B may provoke exit from mitosis coincident with the loss of SIRT2 via ubiquitination and subsequent degradation by the 26S proteasome [4].
• Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle [4].
• A CDC14B mutant defective in catalyzing dephosphorylation fails to change the phosphorylation status or abundance of SIRT2 protein [4].

Biological context of SIRT2

• Cells stably overexpressing the wild-type SIRT2 but not missense mutants lacking NDAC activity show a marked prolongation of the mitotic phase of the cell cycle [4].
• The SIRT2 protein is a NAD-dependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G(2)/M transition of the cell cycle [4].
• Using cell-based assays and RNA interference, we show that puromycin-induced cell death is greatly diminished by nicotinamide (a potent sirtuin inhibitor), and by decreased expression of sirtuins SIRT2 and SIRT3 [5].
• Our identification of putative nuclear export sequences in numerous vertebrate SIRT2 proteins shows that active nuclear export can be a conserved mechanism for regulating Sir2 homologues [6].
• Determination of the exon-intron splice junctions found the full-length SIRT2 protein to consist of 16 exons ranging in size from 16 bp (exon 1) to 749 bp (exon 9) [2].

Associations of SIRT2 with chemical compounds

• On the basis of our results, a phenol moiety on the active compound is suggested to be important for SIRT2 inhibitory activity [7].

Co-localisations of SIRT2

• Type 2 human sirtuin (SIRT2) is a NAD(+)-dependent cytoplasmic protein that is colocalized with HDAC6 on microtubules [7].

Other interactions of SIRT2

• Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2 [8].
• FISH-mapping and genomic organization of the NAD-dependent histone deacetylase gene, Sirtuin 2 (Sirt2) [2].
• Taken together, the findings may represent or lead to cytoskeletal impairment; aberrant antioxidant proteins, chaperons, MAP kinase kinase 1 and NAD-dependent deacetylase sirtuin-2 may have been involved in pathogenetic mechanisms and altered synaptosomal protein expression possibly reflects synaptic impairment in MTLE [9].

Analytical, diagnostic and therapeutic context of SIRT2

• Subsequent Northern blot analysis revealed that RNA expression of SIRT2 was dramatically diminished in 12 out of 17 gliomas and glioma cell lines, in agreement with proteomic data [1].
• Fluorescence in situ hybridization analysis localized the human Sirt2 gene to chromosome 19q13 [2].

References