Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53-dependent mitotic catastrophe.

Abstract

Prolonged mitosis due to aberrant chromosome segregation permits cells to enter the G1 phase without cytokinesis and subsequently triggers the p53-dependent cell death program, known as mitotic catastrophe. Cells which fail to go through mitotic catastrophe create aneuploidy, posing a risk of oncogenesis. In the present report, we show that p62-mediated non-canonical activation of Nrf2 leads to the persistent expression of Nqo1, which plays a critical role for p53 stabilization during mitotic catastrophe. With prolonged exposure to nocodazole, a microtubule-depolymerizing agent, p62-deficient HCT116 cells exhibited an accumulation of a polyploid population with a limited appearance of apoptotic cells, which was attributable to the attenuated stabilization of p53. Combinatorial gene manipulation analysis verified that the regulatory cascade with a hierarchy of p62-Keap1-Nrf2-Nqo1 is required for p53 stabilization for mitotic catastrophe. This is consistent with the role of Nqo1 as a gatekeeper for proteasomal degradation of p53. Thus, we demonstrate for the first time the functional connection between the non-canonical Nrf2 pathway and p53-dependent cell death program upon prolonged mitosis.

• Authors: Chi-Bao Bui, Jaekyoon Shin
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 412 Issue 2 Pg. 347-52 (Aug 26 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21821009 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• SQSTM1 protein, human
• Sequestosome-1 Protein
• Tubulin Modulators
• Tumor Suppressor Protein p53
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• Proteasome Endopeptidase Complex
• Nocodazole

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Aneuploidy
• HCT116 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Kelch-Like ECH-Associated Protein 1
• Mitosis
• NAD(P)H Dehydrogenase (Quinone) (biosynthesis)
• NF-E2-Related Factor 2 (metabolism)
• Nocodazole (pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Sequestosome-1 Protein
• Tubulin Modulators (pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)