Investigating the role of Aurora kinases in RAS signaling.
Activating ras mutations are frequently found in malignant tumors of the pancreas, colon, lung and other tissues. RAS activates a number of downstream pathways that ultimately cause cellular transformation. Several recent studies suggested that one of those pathways involves Aurora kinases. Overexpression of Aurora-B kinase can augment transformation by oncogenic RAS, however the mechanism was not determined. The cooperative effect of high levels of Aurora kinase is important since this kinase is frequently overexpressed in human tumors. We have used two Aurora kinase inhibitors to test their effect on RAS signaling. We find that these inhibitors have no effect on the phosphorylation of MEK1/2 or MAPK in response to RAS. Furthermore, inhibiting Aurora kinases in human cancer cells with or without activated RAS did not change the length of the cell cycle nor induce apoptosis suggesting that these kinases do not play a direct role in these key cellular responses to activated RAS. Overexpression of Aurora B can cause cells to become polyploid. Also, inducing polyploidy with cytochalasin D was reported to induce neoplastic transformation, suggesting that Aurora overexpression may cooperate with RAS indirectly by inducing polyploidy. We find that inducing polyploidy with cytochalasin D or blebbistatin does not enhance transformation by oncogenic RAS. Our observations argue against a direct role for Aurora kinases in the RAS-MAPK pathway, and suggest that the polyploid state does not enhance transformation by RAS.
Kosik
Audrey
A
Department of Biological Sciences, University of Toledo, 2801 W. Bancroft Street, MS 601, Toledo, Ohio 43606, USA.
Bekier
Michael E
ME
Katusin
Jamie D
JD
Kaur
Harpreet
H
Zhou
Xiaofeng
X
Diakonova
Maria
M
Chadee
Deborah N
DN
Taylor
William R
WR
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D001549:Benzamides; D006657:Histones; D011799:Quinazolines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins