Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma.

Abstract

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.

• Authors: Tobias Otto, Sebastian Horn, Markus Brockmann, Ursula Eilers, Lars Schüttrumpf, Nikita Popov, Anna Marie Kenney, Johannes H Schulte, Roderick Beijersbergen, Holger Christiansen, Bernd Berwanger, Martin Eilers
• Journal: Cancer cell (Cancer Cell) Vol. 15 Issue 1 Pg. 67-78 (Jan 06 2009) ISSN: 1878-3686 [Electronic] United States
• PMID: 19111882 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• F-Box Proteins
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• Proto-Oncogene Proteins c-myc
• Ubiquitin-Protein Ligases
• AURKA protein, human
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Aurora Kinase A
• Aurora Kinases
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• F-Box Proteins (metabolism)
• F-Box-WD Repeat-Containing Protein 7
• Humans
• Neuroblastoma (genetics, metabolism, pathology)
• Protein Binding
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Interference
• Ubiquitin-Protein Ligases (metabolism)