Depletion of Aurora-A in zebrafish causes growth retardation due to mitotic delay and p53-dependent cell death
- Authors
- Jeon, H.Y., and Lee, H.
- ID
- ZDB-PUB-130204-4
- Date
- 2013
- Source
- The FEBS journal 280(6): 1518-1530 (Journal)
- Registered Authors
- Jeon, Hee-Yeon, Lee, Hyunsook
- Keywords
- Aurora-A, zebrafish, live-imaging, spindle assembly checkpoint (SAC), p53, apoptosis
- MeSH Terms
-
- Animals
- Aurora Kinases
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Death
- Centrosome/enzymology
- Centrosome/metabolism
- Centrosome/pathology
- Cloning, Molecular
- Disease Models, Animal
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/enzymology
- Embryo, Nonmammalian/pathology
- Embryonic Development
- Gene Expression Regulation, Developmental*
- Gene Expression Regulation, Enzymologic
- In Situ Nick-End Labeling
- M Phase Cell Cycle Checkpoints*
- Microinjections
- Microscopy, Fluorescence
- Mitosis
- Morpholinos/administration & dosage
- Morpholinos/metabolism
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- Spindle Apparatus/genetics
- Spindle Apparatus/metabolism*
- Time Factors
- Time-Lapse Imaging/methods
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism*
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 23351126 Full text @ FEBS J.
Aurora-A is a serine/threonine mitotic kinase that is required for centrosome maturation. Many cancer cells overexpress 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 done 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 the homeostasis of spindle organization in mitosis using zebrafish embryogenesis as a model system. Using morpholino technology, we show that the depletion of Aurora-A in zebrafish embryogenesis results in short and bended 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, which are manifested through monopolar and disorganized spindle formation. Aurora-A-depleted cells exhibited mitotic arrest with congression failure, leading to the 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 cancers with intact p53 may be the targets for Aurora-A inhibitors.