Aurora-A kinase interacting protein (AIP), a novel negative regulator of human Aurora-A kinase.
Aurora kinases have evolved as a new family of mitotic centrosome- and microtubule-associated kinases that regulate the structure and function of centrosomes and spindle. One of its members, Aurora-A, is a potential oncogene. Overexpression of Aurora-A is also implicated in defective centrosome duplication and segregation, leading to aneuploidy and tumorigenesis in various cancer cell types. However, the regulatory pathways for mammalian Aurora-A are not well understood. Exploiting the lethal phenotype associated with the overexpression of Aurora-A in yeast, we performed a dosage suppressor screen in yeast and report here the identification of a novel negative regulator of Aurora-A, named AIP (Aurora-A kinase Interacting Protein). AIP is a ubiquitously expressed nuclear protein that interacts specifically with human Aurora-A in vivo. Ectopic expression of AIP with Aurora-A in NIH 3T3 and COS cells results in the down-regulation of ectopically expressed Aurora-A protein levels, and this down-regulation is demonstrated to be the result of destabilization of Aurora-A through a proteasome-dependent protein degradation pathway. A noninteracting deletion mutant of AIP does not down-regulate Aurora-A protein, suggesting that the interaction is important for the protein degradation. AIP could therefore be a potential useful target gene for anti-tumor drugs.
Kiat
Lim Shen
LS
Division of Cellular and Molecular Research, National Cancer Centre, Singapore 169610.
Hui
Kam Man
KM
Gopalan
Ganesan
G
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D016415:Sequence Alignment; D014018:Tissue Distribution; D029867:Xenopus Proteins
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011506:Proteins; D029867:Xenopus Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D011494:Protein Kinases; C112134:AURKA protein, Xenopus; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex