Depletion of Aurora-A in zebrafish causes growth retardation due to mitotic delay and p53-dependent cell death.
Aurora-A is a serine/threonine mitotic kinase that is required for centrosome maturation. Many cancer cells over-express Aurora-A, and several reports have suggested that Aurora-A has prognostic value in the clinical treatment of cancer. Therefore, inhibitors for Aurora-A kinase have been developed. However, studies on Aurora-A are largely performed in cancer cell lines and are sometimes controversial. For effective evaluation of Aurora-A inhibitors in cancer treatment, it is essential to understand its function at the organism level. Here, we report the crucial functions of Aurora-A in homeostasis of spindle organization in mitosis using zebrafish embryogenesis as a model system. Using morpholino technology, we show that depletion of Aurora-A in zebrafish embryogenesis results in short bent trunks, accompanied by growth retardation and eventual cell death. Live-imaging and immunofluorescence analyses of the embryos revealed that the developmental defects are due to problems in mitosis, manifested through monopolar and disorganized spindle formation. Aurora-A-depleted cells exhibited mitotic arrest with congression failure, leading to activation of the spindle assembly checkpoint. Cell death in the absence of Aurora-A was partially rescued by co-injection of the p53 morpholino, suggesting that apoptosis after Aurora-A depletion is p53-dependent. The clinical implications of these results relate to the indication that Aurora-A inhibitors may be effective towards cancers with intact p53.
Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea.
Hee-Yeon
HY
Jeon
Hyunsook
H
Lee
D000818:Animals; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D018385:Centrosome / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D020287:In Situ Nick-End Labeling; D059566:M Phase Cell Cycle Checkpoints; D008845:Microinjections; D008856:Microscopy, Fluorescence; D008938:Mitosis; D060172:Morpholinos / Q000008:administration & dosage / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D059008:Time-Lapse Imaging / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D060172:Morpholinos; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases