Aurora B kinase phosphorylates and instigates degradation of p53.

Abstract

Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly interacts with p53 at different subcellular localizations and during different phases of the cell cycle (for instance, at the nucleus in interphase and the centromeres in prometaphase of mitosis). We show that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic inhibition of Aurora B in cancer cells with WT p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results define a mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of Aurora B may compromise the tumor suppressor function of p53. We have elucidated the antineoplastic mechanism for Aurora B kinase inhibitors in cancer cells with WT p53.

• Authors: Chris P Gully, Guermarie Velazquez-Torres, Ji-Hyun Shin, Enrique Fuentes-Mattei, Edward Wang, Colin Carlock, Jian Chen, Daniel Rothenberg, Henry P Adams, Hyun Ho Choi, Sergei Guma, Liem Phan, Ping-Chieh Chou, Chun-Hui Su, Fanmao Zhang, Jiun-Sheng Chen, Tsung-Ying Yang, Sai-Ching J Yeung, Mong-Hong Lee
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 24 Pg. E1513-22 (Jun 12 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22611192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Tumor Suppressor Protein p53
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Aurora Kinase B
• Aurora Kinases
• Humans
• Interphase
• Mitosis
• Phosphorylation
• Protein Binding
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proteolysis
• Subcellular Fractions (enzymology, metabolism)
• Transcription, Genetic
• Tumor Suppressor Protein p53 (metabolism)
• Ubiquitination