Analysis of Aurora B Regulation and Signaling

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Title: Analysis of Aurora B Regulation and Signaling
Author: Oncel, Dilhan
Abstract: Aurora B is a serine /threonine kinase that functions in a complex with two other chromosomal passenger proteins called INCENP and Survivin . Its function is implicated in a variety of processes related to mitosis , such as chromosome condensation , regulation of arm cohesion , spindle assembly , chromosome bi -orientation and cytokinesis . During the cell cycle , the level of this protein is tightly controlled and its deregulated abundance is suspected to contribute to aneuploidy . The cell cycle profile for Aurora B is reminiscent of those for substrates of the anaphase -promoting complex /cyclosome (APC /C ) , an ubiquitin ligase essential for mitotic progression . Here , we showed that Aurora B is a substrate of APC /C both in vitro and in vivo . Aurora B is efficiently ubiquitinated iv in an in vitro reconstituted system by APC /C that had been activated by Cdh1 . The recognition of Aurora B by APC /CCdh1 is specific as it requires the presence of a conserved KEN -box motif at the amino terminus of Aurora B . Degradation of Aurora B at the end of mitosis requires Cdh1 in vivo as the reduction of Cdh1 level by RNA interference stabilizes Aurora B protein . We conclude that , as a key mitotic regulator , Aurora B is degraded by APC /CCdh1 in late mitosis . Aurora B lies at the heart of the cellular mechanism that resolves synthelic and merotelic attachments . A failure to eliminate such events results in gain or loss of chromosomes . Therefore , identifying the physiological substrates of Aurora B is of pivotal importance for research . We screened Aurora B substrates using an in vitro expression cloning system . However , the methodology we employed didn't lead to candidate substrates to be further validated by more rigorous in vivo approaches . The use of high concentrations of misfolded recombinant Aurora B was partially responsible for the loss of specificity . Therefore , purifying active recombinant Aurora B has become a primary goal for future biochemical and structural work . Two molecular chaperones Hsp90 and Cdc37 assist the folding of a variety of kinases in vivo , among which Aurora B is also a candidate . This gave us the final idea of expressing Aurora B -INCENP complexes in bacteria via the coexpression of Hsp90 -Cdc37 molecular chaperones .
URI: http : / /hdl .handle .net /2152 .5 /591
Date: 2006-05-16


Analysis of Aurora B Regulation and Signaling. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /591 .

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