control of centrin stability by aurora a控制centrin稳定的极光.pdfVIP

Control of Centrin Stability by Aurora A 1¤ 1 2 2 1 Kara B. Lukasiewicz , Tammy M. Greenwood , Vivian C. Negron , Amy K. Bruzek , Jeffrey L. Salisbury *, Wilma L. Lingle1,2* 1 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America, 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America Abstract Aurora A is an oncogenic serine/threonine kinase which can cause cell transformation and centrosome amplification when over-expressed. Human breast tumors show excess Aurora A and phospho-centrin in amplified centrosomes. Here, we show that Aurora A mediates the phosphorylation of and localizes with centrin at the centrosome, with both proteins reaching maximum abundance from prophase through metaphase, followed by their precipitous loss in late stages of mitosis. Over- expression of Aurora A results in excess phospho-centrin and centrosome amplification. In contrast, centrosome amplification is not seen in cells over-expressing Aurora A in the presence of a recombinant centrin mutant lacking the serine phosphorylation site at residue 170. Expression of a kinase dead Aurora A results in a decrease in mitotic index and abrogation of centrin phosphorylation. Finally, a recombinant centrin mutation that mimics centrin phosphorylation increases centrin’s stability against APC/C-mediated proteasomal degradation. Taken together, these results suggest that the stability of centrin is regulated in part by Aurora A, and that excess phosphorylated centrin may promote centrosome amplification in cancer. Citation: Lukasiewicz KB, Greenwood TM, Negron