Aurora A is essential for early embryonic development and tumor suppression.
Aurora A is a serine/threonine kinase that functions in various stages of mitosis. Accumulating evidence has demonstrated that gene amplification and overexpression of Aurora A are linked to tumorigenesis, suggesting that Aurora A is an oncogene. In addition, Aurora A overexpression has been used as a negative prognostic marker, because it is associated with resistance to anti-mitotic agents commonly used for cancer therapy. To understand the physiological functions of Aurora A, we generated Aurora A knock-out mice. Aurora A null mice die early during embryonic development before the 16-cell stage. These Aurora A null embryos have defects in mitosis, particularly in spindle assembly, supporting critical functions of Aurora A during mitotic transitions. Interestingly, Aurora A heterozygosity results in a significantly increased tumor incidence in mice, suggesting that Aurora A may also act as a haploinsufficient tumor suppressor. Consistently, Aurora A heterozygous mouse embryonic fibroblasts have higher rates of aneuploidy. We further discovered that VX-680, an Aurora kinase inhibitor currently in phase II clinical trials for cancer treatment, could induce aneuploidy in wild type mouse embryonic fibroblasts. We conclude that a balanced Aurora A level is critical for maintaining genomic stability and one needs to be fully aware of the potential side effects of anti-cancer therapy based on the use of Aurora A-specific inhibitors.
Lu
Lin-Yu
LY
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Wood
Jamie L
JL
Ye
Lin
L
Minter-Dykhouse
Katherine
K
Saunders
Thomas L
TL
Yu
Xiaochun
X
Chen
Junjie
J
D000782:Aneuploidy; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004622:Embryo, Mammalian / Q000196:embryology / Q000201:enzymology; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064096:Aurora Kinase A; D064127:Aurora Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576918:Aurka protein, mouse
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