Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma.
In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. In a shRNA screen of genes that are highly expressed in MYCN-amplified tumors, we have identified AURKA as a gene that is required for the growth of MYCN-amplified neuroblastoma cells but largely dispensable for cells lacking amplified MYCN. Aurora A has a critical function in regulating turnover of the N-Myc protein. Degradation of N-Myc requires sequential phosphorylation by cyclin B/Cdk1 and Gsk3. N-Myc is therefore degraded during mitosis in response to low levels of PI3-kinase activity. Aurora A interacts with both N-Myc and the SCF(Fbxw7) ubiquitin ligase that ubiquitinates N-Myc and counteracts degradation of N-Myc, thereby uncoupling N-Myc stability from growth factor-dependent signals.
Otto
Tobias
T
Institute of Molecular Biology and Tumor Research, Marburg, Germany.
Horn
Sebastian
S
Brockmann
Markus
M
Eilers
Ursula
U
Schüttrumpf
Lars
L
Popov
Nikita
N
Kenney
Anna Marie
AM
Schulte
Johannes H
JH
Beijersbergen
Roderick
R
Christiansen
Holger
H
Berwanger
Bernd
B
Eilers
Martin
M
D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016271:Proto-Oncogene Proteins c-myc; D044767:Ubiquitin-Protein Ligases; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases