A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73.

Protein degradation is an essential and highly regulated process. The proteasomal degradation of the tumor suppressors p53 and p73 is regulated by both polyubiquitination and by an ubiquitin-independent process. Here, we show that this ubiquitin-independent process is mediated by the 20S proteasomes and is regulated by NQO1. NQO1 physically interacts with p53 and p73 in an NADH-dependent manner and protects them from 20S proteasomal degradation. Remarkably, the vast majority of NQO1 in cells is found in physical association with the 20S proteasomes, suggesting that NQO1 functions as a gatekeeper of the 20S proteasomes. We further show that this pathway plays a role in p53 accumulation in response to ionizing radiation. Our findings provide the first evidence for in vivo degradation of p53 and p73 by the 20S proteasomes and its regulation by NQO1 and NADH level.

[1]  Robert E. Cohen,et al.  Proteasomes and their kin: proteases in the machine age , 2004, Nature Reviews Molecular Cell Biology.

[2]  J. Lotem,et al.  p53-dependent apoptosis and NAD(P)H:quinone oxidoreductase 1. , 2004, Methods in enzymology.

[3]  A. Goldberg,et al.  Protein degradation and protection against misfolded or damaged proteins , 2003, Nature.

[4]  Xiaoyong Yang,et al.  O-GlcNAc Modification Is an Endogenous Inhibitor of the Proteasome , 2003, Cell.

[5]  J. Lotem,et al.  p53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[6]  David Siegel,et al.  Interaction of Human NAD(P)H:Quinone Oxidoreductase 1 (NQO1) with the Tumor Suppressor Protein p53 in Cells and Cell-free Systems* , 2003, The Journal of Biological Chemistry.

[7]  J. Lotem,et al.  Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Lotem,et al.  NQO1 stabilizes p53 through a distinct pathway , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  B. Friguet,et al.  Redox control of 20S proteasome. , 2002, Methods in enzymology.

[10]  A. Multani,et al.  Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia. , 2002, Cancer research.

[11]  J. Lotem,et al.  Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[13]  R. Deshaies,et al.  A Proteasome Howdunit The Case of the Missing Signal , 2000, Cell.

[14]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[15]  W. Baumeister,et al.  A Subcomplex of the Proteasome Regulatory Particle Required for Ubiquitin-Conjugate Degradation and Related to the COP9-Signalosome and eIF3 , 1998, Cell.

[16]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[17]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[18]  A. Hershko.  Lessons from the discovery ofthe ubiquitin system , 1996 .

[19]  A. Hershko.  Lessons from the discovery of the ubiquitin system. , 1996, Trends in biochemical sciences.

[20]  K Tanaka,et al.  Structure and functions of the 20S and 26S proteasomes. , 1996, Annual review of biochemistry.

[21]  C. Kahana,et al.  A unified pathway for the degradation of ornithine decarboxylase in reticulocyte lysate requires interaction with the polyamine-induced protein, ornithine decarboxylase antizyme. , 1994, European journal of biochemistry.

[22]  D. Chowdary,et al.  Accumulation of p53 in a mutant cell line defective in the ubiquitin pathway , 1994, Molecular and cellular biology.

[23]  A. Y. Lu,et al.  Identification of a glycine-rich sequence as an NAD(P)H-binding site and tyrosine 128 as a dicumarol-binding site in rat liver NAD(P)H:quinone oxidoreductase by site-directed mutagenesis. , 1992, The Journal of biological chemistry.

[24]  K. Hayashi,et al.  Properties and reaction mechanism of DT diaphorase from rat liver. , 1974, The Journal of biological chemistry.