tailieunhanh - Báo cáo khoa học: Mammalian mitotic centromere-associated kinesin (MCAK) A new molecular target of sulfoquinovosylacylglycerols novel antitumor and immunosuppressive agents

Sulfoquinovosylacylglycerols (SQAGs), in particular compounds with C18 fatty acid(s) on the glycerol moiety, may be clinically promising antitumor and⁄or immunosuppressive agents. They were found originally as inhibitors of mammalian DNA polymerases. However, SQAGs can arrest cultured mammalian cells not only at S phase but also at M phase, suggesting they have several molecular targets. | iFEBS Journal Mammalian mitotic centromere-associated kinesin MCAK A new molecular target of sulfoquinovosylacylglycerols novel antitumor and immunosuppressive agents Satoko Aoki1 2 Keisuke Ohta1 Takayuki Yamazaki1 Fumio Sugawara1 2 and Kengo Sakaguchi1 2 1 Department of Applied BiologicalScience Tokyo University of Science Noda Chiba Japan 2 Genome and Drug Research Center Tokyo University of Science Noda Chiba Japan Keywords mammalian DNA polymerases MT depolymerization activity of MCAK SQAGs T7 phage display method Correspondence K. Sakaguchi Department of Applied BiologicalScience Tokyo University of Science 2641 Yamazaki Noda Chiba 2788510 Japan Fax 81 4 7123 9767 Tel 81 4 7124 1501 ext. 3409 E-mail kengo@ Received 30 October 2004 revised 20 January 2005 accepted 7 February 2005 doi Sulfoquinovosylacylglycerols SQAGs in particular compounds with C18 fatty acid s on the glycerol moiety may be clinically promising antitumor and or immunosuppressive agents. They were found originally as inhibitors of mammalian DNA polymerases. However SQAGs can arrest cultured mammalian cells not only at S phase but also at M phase suggesting they have several molecular targets. A screen for candidate target molecules using a T7 phage display method identified an amino acid sequence. An homology search showed this to be a mammalian mitotic centromere-associated kinesin MCAK rather than a DNA polymerase. Analyses showed SQAGs bound to recombinant MCAK with a KD X 10 4 to X 10 5 M. An in vivo microtubule depolymerization assay using EGFP-full length MCAK fusion constructs indicated inhibition of the microtubule depolymerization activity of MCAK. From these results we conclude that clinically promising SQAGs have at least two different molecular targets DNA polymerases and MCAK. It should be stressed that inhibitors of MCAK have never been reported previously so that there is a major potential for clinical utility. Several .