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A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73
Open accessAbstract
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.
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“Interestingly, the reduced form of NAD+, NADH, binds and stabilizes 26S proteasomes, and may also regulate the function of 20S proteasomes, the two main proteolytic complexes (Asher et al., 2005; Tsvetkov et al., 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Asher et al., 2005
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“The tumor suppressor p53 is a very labile protein that undergoes Mdm2 and ubiquitin-dependent 26S proteasomal degradation (Haupt et al. 1997; Kubbutat et al. 1997).”
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“Besides, TAp73 and DNp73 have also been shown to be regulated by nonclassical pathways such as calpain cleavage (14), and by the NQO1 (15), UFD2a (16), and cyclin G–dependent (17), proteasomemediated pathways.”
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Sayan, E., Sayan, B. S., Gogvadze, V. G., Dinsdale, D. D., Nyman, U., Hansen, T. M., Zhivotovsky, B., Cohen, G. M., Knight, R. A., & Melino, G. (2008) · Oncogene · doi:10.1038/onc.2008.64 · Cited by 60
“p73 is also subjected to ubiquitinindependent 20S proteasomal degradation that is regulated by NAD(P)H quinone oxidoreductase 1 together with NADH (Asher et al., 2005).”
InfluentialTAp73 is a marker of glutamine addiction in medulloblastomaPreprint
Niklison-Chirou, M. V., Erngren, I., Engskog, M. K. R., Haglöf, J., Picard, D. J., Remke, M., McPolin, P. H. R., Selby, M. P., Williamson, D., Clifford, S. C., et al. (2017) · Genes & Development · doi:10.1101/gad.302349.117 · Cited by 61
“Since increased levels of p73 can induce apoptosis (Asher et al. 2005), we measured apoptosis with Annexin/PI in DAOY and UW228-2 cells under the different starvation conditions.”
The Annexin A2/S100A10 Complex: The Mutualistic Symbiosis of Two Distinct Proteins
Bharadwaj, A. G., Kempster, E., & Waisman, D. M. (2021) · Biomolecules · doi:10.3390/biom11121849 · Cited by 58
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“Indeed, a regulatory role on the proteosomal degradation of proteins controlling cell growth, differentiation, and death (including p53, p73 a and ornithine decarboxylase) has recently been demonstrated (13, 14).”
Faust, T. B., Binning, J. M., Gross, J. D., & Frankel, A. D. (2017) · Annual Review of Virology · doi:10.1146/annurev-virology-101416-041654 · Cited by 64
Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism
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NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation
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“Furthermore, NQO1 participates in the stability of other proteins such as p33ING1b and p73 (Asher et al., 2005; Garate et al., 2008), indicating that NQO1 acts as a protein chaperone.”
BackgroundZhou, H., Zeng, H., Yuan, D., Ren, J., Cheng, S., Yu, H., Ren, F., Wang, Q., Qin, Y.-P., Huang, A., et al. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0491-7 · Cited by 56
“On the other hand, NQO1 has been reported to regulate proteasomal degradation in a NADH-dependent manner [40].”
BackgroundEngelmann, D., Meier, C., Alla, V., & Pützer, B. M. (2014) · Oncogene · doi:10.1038/onc.2014.365 · Cited by 53
Tsvetkov, P., Reuven, N. B., Prives, C. L., & Shaul, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.040493 · Cited by 55
Self-citationGarate, M., Wani, A. A., & Li, G. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.03.003 · Cited by 54
“It has been previously demonstrated that NQO1 binds and stabilizes different target proteins inhibiting their proteasome degradation [38,54].”
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“to cells has been shown to target p53 and other client proteins for degradation [6-8, 11, 12].”
BackgroundInfluentialDegrons: defining the rules of protein degradation
Zhang, Z., Mena, E. L., Timms, R. T., Koren, I., & Elledge, S. J. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00870-z · Cited by 67
“A variety of other proteins have also been proposed to undergo ubiquitin-independent degradation 24,25,144–153 , but only recently has definitive evidence emerged of a wider role for this pathway.”
RNAP II CTD tyrosine 1 performs diverse functions in vertebrate cells
Hsin, J.-P., Li, W., Hoque, M., Tian, B., & Manley, J. L. (2014) · eLife · doi:10.7554/elife.02112 · Cited by 53
“In vitro proteasome assays were performed as described (31) with the following modifications.”
MethodMyers, N., Olender, T., Savidor, A., Levin, Y., Reuven, N. B., & Shaul, Y. (2018) · PROTEOMICS · doi:10.1002/pmic.201800076 · Cited by 53
Self-citationProteasomal Degradation Machinery: Favorite Target of HIV-1 Proteins
Lata, S., Mishra, R., & Banerjea, A. C. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02738 · Cited by 58
Therapeutic prospects for p73 and p63: Rising from the shadow of p53
Vilgelm, A. E., El-Rifai, W. M., & Zaika, A. I. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.08.001 · Cited by 53
“Both enzymes affect the levels of p73 during DNA damage (Asher et al., 2005; Hosoda et al., 2005).”
BackgroundLim, S. K., & Gopalan, G. (2007) · Biochemical Journal · doi:10.1042/bj20061272 · Cited by 55
Mechanisms of Protein Degradation: An Odyssey with ODC
Kahana, C., Asher, G., & Shaul, Y. (2005) · Cell Cycle · doi:10.4161/cc.4.11.2115 · Cited by 52
Self-citationLactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth
Rao, K., Zhang, X., Luo, Y., Xia, Q., Jin, Y., & He, J. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115441 · Cited by 54
González‐Aragón, D., Ariza, J., & Villalba, J. M. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.10.016 · Cited by 51
NADH binds and stabilizes the 26S proteasomes independent of ATP
Tsvetkov, P., Myers, N., Eliav, R., Adamovich, Y., Hagai, T., Adler, J., Navon, A., & Shaul, Y. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.537175 · Cited by 42
“Given the involvement of NAD(H) in proteasomal degradation (13, 14), we explored the possibility that NAD(H) regulates the proteasomal complex integrity and function.”
BackgroundSelf-citationImpact of NQO1 dysregulation in CNS disorders
Li, Y., Ghadiri, M. K., & Gorji, A. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-023-04802-3 · Cited by 53
“Furthermore, studies on fractionated mouse liver extracts and human colon carcinoma cells have revealed that NQO1 can directly reduce superoxide and modulate the degradation of some proteins, such as P53 [19, 29].”
BackgroundBasbous, J., Jariel‐Encontre, I., Gomard, T., Bossis, G., & Piechaczyk, M. (2007) · Biochimie · doi:10.1016/j.biochi.2007.07.016 · Cited by 50
Sollner, S., Nebauer, R., Ehammer, H., Prem, A., Deller, S., Palfey, B. A., Daum, G., & Macheroux, P. (2007) · FEBS Journal · doi:10.1111/j.1742-4658.2007.05682.x · Cited by 49
Song, I.-K., Lee, J., Cho, J., Jeong, J., Shin, D. H., & Lee, K. (2016) · Scientific Reports · doi:10.1038/srep34432 · Cited by 50
“Some proteins including p53 and p73 are regulated by both ubiquitin-dependent and –independent pathways 51 .”
Post-translational regulation of p53 function through 20S proteasome-mediated cleavage
Solomon, H., Bräuning, B., Fainer, I., Ben‐Nissan, G., Rabani, S., Goldfinger, N., Moscovitz, O., Shakked, Z., Rotter, V., & Sharon, M. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.139 · Cited by 50
Prawan, A., Buranrat, B., Kukongviriyapan, U., Sripa, B., & Kukongviriyapan, V. (2008) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-008-0483-2 · Cited by 47
“Moreover, NQO1 is physically associated with 20S proteasomes, and this association prevents the degradation of p53 and p73, the tumor suppressor proteins ( Asher et al. 2005 ).”
BackgroundMedina‐Carmona, E., Palomino‐Morales, R., Fuchs, J. E., Padín-González, E., Mesa‐Torres, N., SALIDO, E. C., Timson, D. J., & Pey, A. L. (2016) · Scientific Reports · doi:10.1038/srep20331 · Cited by 47
NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Localizes to the Mitotic Spindle in Human Cells
Siegel, D. M., Kepa, J. K., & Ross, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044861 · Cited by 47
Waku, T., Nakamura, N., Koji, M., Watanabe, H., Katoh, H., Tatsumi, C., Tamura, N., Hatanaka, A., Hirose, S., Katayama, H., et al. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00597-19 · Cited by 47
“tumor suppressors, including p53 and retinoblastoma protein (Rb) (4, 5).”
BackgroundMethodLata, S., Ali, A., Sood, V., Raja, R., & Banerjea, A. C. (2015) · Nature Communications · doi:10.1038/ncomms8244 · Cited by 47
Adler, J., Reuven, N. B., Kahana, C., & Shaul, Y. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00899-09 · Cited by 46
“NQO1 physically interacts with and protects the IUPs, such as p53, p73 , and ODC, from degradation (2, 8).”
BackgroundMethodInfluentialSelf-citationPandareesh, M. D., Shrivash, M. K., Kumar, H. N. N., Misra, K., & Bharath, M. M. S. (2016) · Neurochemical Research · doi:10.1007/s11064-016-2034-6 · Cited by 46
AMPK couples p73 with p53 in cell fate decision
Adamovich, Y., Adler, J., Meltser, V., Reuven, N. B., & Shaul, Y. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.60 · Cited by 44
“The protein steady-state level of p73 is also controlled by ubiquitinindependent degradation by the 20S proteasome.(22) Interest-”
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van IJzendoorn, D. G. P., Forghany, Z., Liebelt, F., Vertegaal, A. C. O., Jochemsen, A. G., Bovée, J. V. M. G., Szuhai, K., & Baker, D. A. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.c117.815845 · Cited by 44
“Cell-free degradation assays were performed as described previously (16).”
Methodp73: A chiaroscuro gene in cancer
Marabese, M., Vikhanskaya, F., & Broggini, M. (2007) · European Journal of Cancer · doi:10.1016/j.ejca.2007.01.042 · Cited by 43
The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system
Chen, G., Wang, Y., Garate, M., Zhou, J., & Li, G. (2009) · Oncogene · doi:10.1038/onc.2009.424 · Cited by 43
“5% PAGE, where the 26S proteasome complex was identified by overlay staining using the fluorogenic substrate Suc-LLVY-AMC (BIOMOL International, Plymouth Meeting, PA, USA) as described (Asher et al., 2005).”
MethodSite-Specific Methionine Oxidation Initiates Calmodulin Degradation by the 20S Proteasome
Balog, E. M., Lockamy, E. L., Thomas, D. D., & Ferrington, D. A. (2009) · Biochemistry · doi:10.1021/bi802117k · Cited by 46
“Other mechanisms for tethering substrates to either the 26S and 20S proteasomes are the ATPase subunits of PA700 and adaptor molecules that bind to the 20S, such as HSP90 or NAD(P)H quinone oxidoreductase 1, that recognize unfolded proteins or specific protein substrates (11, 42, 43).”
BackgroundJung, Y.-S., Qian, Y., & Chen, X. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.261537 · Cited by 42
Siegel, D. M., Dehn, D. L., Bokatzian, S. S., Quinn, K. D., Backos, D. S., Francesco, A. D., Bernier, M., Reisdorph, N. A., de Cabo, R., & Ross, D. (2018) · PLoS ONE · doi:10.1371/journal.pone.0190717 · Cited by 42
Quinone reductase acts as a redox switch of the 20S yeast proteasome
Sollner, S., Schober, M., Wagner, A., Prem, A., Lorkova, L., Palfey, B. A., Groll, M., & Macheroux, P. (2008) · EMBO Reports · doi:10.1038/embor.2008.218 · Cited by 41
“As shown previously, Lot6 catalyses the reduction of a series of quinones at the expense of both NADH and NADPH (Sollner et al, 2007).”
BackgroundMethodInfluentialHu, L., Wang, J., Liu, Y., Zhang, Y., Zhang, L., Kong, R., Zheng, Z., Du, X., & Ke, Y. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.157842 · Cited by 41
Proteasome Activation to Combat Proteotoxicity
Jones, C. L., & Tepe, J. J. (2019) · Molecules · doi:10.3390/molecules24152841 · Cited by 43
“While both the UPS and UIPS may target IDPs for degradation (a specific example of UIPS targeting IDPs is p53 and p73 [187] and other evidence is available [191–195]), the UPS targets structured and misfolded proteins in need of removal, [151,196–198] whereas the UIPS is restricted to the removal of oxidatively damage…”
BackgroundRole of proteasomes in transcription and their regulation by covalent modifications
Mittenberg, A. G. (2008) · Frontiers in bioscience · doi:10.2741/3220 · Cited by 40
“7186 mediated by NQO1, a NADH-dependent oxidase, which serves as a “gatekeeper” of the 20S proteasome (30, 31).”
BackgroundMorozov, A. V., Astakhova, T. M., Garbuz, D. G., Krasnov, G. S., Bobkova, N. V., Zatsepina, O. G., Карпов, В. Л., & Evgen’ev, M. B. (2017) · Cell Stress and Chaperones · doi:10.1007/s12192-017-0792-y · Cited by 39
“Here, it should be mentioned that both ubiquitin dependent and independent degradation of the same substrates was demonstrated (Asher et al. 2005; Ben-Nissan and Sharon 2014).”
The dual role of p62 in ferroptosis of glioblastoma according to p53 status
Yuan, F., Sun, Q., Zhang, S., Ye, L., Xu, Y., Deng, G., Xu, Z., Zhang, S., Liu, B., & Chen, Q. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00764-z · Cited by 39
“Secondly, there are many different mutations in p53 and does the dual function of p62 on ferroptosis suits for other kinds of p53 mutation? Thirdly, is it possible that NRF2 affects p53 signaling in a feedback loop mediated by p62? Previous findings from the Shaul lab indicate that NQO1, an NRF2 target, interacts with…”
BackgroundAlard, A., Fabre, B., Anesia, R., Marbœuf, C., Pierre, P., Susini, C., Bousquet, C., & Pyronnet, S. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00868-09 · Cited by 39
“NQO1 has been shown previously to protect four different proteins, p53 and p73 (3), ODC (1), and p33 (13), from degradation by the proteasome.”
BackgroundNQO1 protects obese mice through improvements in glucose and lipid metabolism
Francesco, A. D., Choi, Y., Bernier, M., Zhang, Y., Díaz‐Ruiz, A., Aon, M. A., Kalafut, K. C., Ehrlich, M. R., Murt, K. N., Ali, A., et al. (2020) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-020-00051-6 · Cited by 40
Role of PGC-1α in the Mitochondrial NAD+ Pool in Metabolic Diseases
Koh, J., & Kim, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094558 · Cited by 39
Medina‐Carmona, E., Neira, J. L., SALIDO, E. C., Fuchs, J. E., Palomino‐Morales, R., Timson, D. J., & Pey, A. L. (2017) · Scientific Reports · doi:10.1038/srep44532 · Cited by 37
“…we show that neither the CTD nor an active NQO1 is strictly required to interact with p73 α , even though different ligands bound to NQO1 may modulate the intrinsically low affinity of this interaction, consistent with previous biochemical studies on these protein:protein interactions 29,30,37,41 .”
InfluentialHe, Y., Feng, D., Hwang, S., Mackowiak, B., Wang, X., Xiang, X., Rodrigues, R. M., Fu, Y., Ma, J., Ren, T., et al. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.02.004 · Cited by 36
DEGRONOPEDIA: a web server for proteome-wide inspection of degrons
Szulc, N. A., Stefaniak, F., Piechota, M., Soszyńska, A., Piórkowska, G., Cappannini, A., Bujnicki, J. M., Maniaci, C., & Pokrzywa, W. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae238 · Cited by 35
JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress
Kostecka, A., Sznarkowska, A., Meller, K., Acedo, P., Shi, Y., Sakil, H. A. M., Kawiak, A., Lion, M., Królicka, A., Wilhelm, M., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.408 · Cited by 35
“We reasoned that ROS induced by WA might promote TAp73 protein stabilization as NQO1, which expression depends on the oxidative status of the cell, was found to have a key role in ablating theUb (ubiquitin)-independent degradation of p53 and TAp73.”
BackgroundInfluentialCalpain cleavage regulates the protein stability of p73
Munarriz, E. R., Bano, D., Sayan, E., Rossi, M., Melino, G., & Nicotera, P. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.188 · Cited by 35
Sollner, S., & Macheroux, P. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07143.x · Cited by 35
Grillari, J., Grillari‐Voglauer, R., & Jansen‐Dürr, P. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-7002-2_13 · Cited by 36
Bunjobpol, W., Dulloo, I., Igarashi, K., Concin, N., Matsuo, K., & Sabapathy, K. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.41 · Cited by 34
Medina‐Carmona, E., Fuchs, J. E., Gavira, J. A., Mesa‐Torres, N., Neira, J. L., SALIDO, E. C., Palomino‐Morales, R., Burgos, M., Timson, D. J., & Pey, A. L. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx238 · Cited by 33
“NQO1 is a homodimeric FAD-dependent enzyme involved in the activation of some anti-cancer pro-drugs (41,46), which also interacts with and stabilizes transcription factors associated with cancer and cell-cycle regulation, such as p53, p73a and HIF-1a (47,48).”
BackgroundThree‑microRNA expression signature predicts survival in triple‑negative breast cancer
Wu, X., Ding, M., & Lin, J. (2019) · Oncology Letters · doi:10.3892/ol.2019.11118 · Cited by 36
“Enhanced ubiquitin-mediated proteolysis causes the rapid hydrolysis of proteins, including tumor protein p53 and interferon α inducible protein 27, which are closely associated with invasiveness, malignancy, clinical stage and poor prognosis in breast cancer (49).”
BackgroundAnoz‐Carbonell, E., Timson, D. J., Pey, A. L., & Medina, M. (2020) · Antioxidants · doi:10.3390/antiox9090772 · Cited by 34
“In addition, NQO1 is capable of interacting with over forty different proteins, such as p53, p73α and HIF-1α, and the general effect of these interactions is the protection of protein partners against proteasomal degradation [4,15,16].”
BackgroundProteasome-dependent degradation of α-catenin is regulated by interaction with ARMc8α
Suzuki, T., Ueda, A., Kobayashi, N., Yang, J. H., Tomaru, K., Yamamoto, M., Takeno, M., & Ishigatsubo, Y. (2008) · Biochemical Journal · doi:10.1042/bj20071312 · Cited by 34
Fagerholm, R., Sprott, K. M., Heikkinen, T., Bártková, J., Heikkilä, P., Aittomäki, K., Bártek, J., Weaver, D. T., BLOMQVIST, C. P., & Nevanlinna, H. A. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt290 · Cited by 37
“In addition to its role in the management of ROS, it stabilizes key stress response proteins such as p53 and p73 and modulates the NFκB pathway [14–16].”
BackgroundExpression of TP53 Isoforms p53β or p53γ Enhances Chemosensitivity in TP53null Cell Lines
Silden, E., Hjelle, S. M., Wergeland, L., Sulen, A., Andresen, V., Bourdon, J., Micklem, D., McCormack, E., & Gjertsen, B. T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056276 · Cited by 33
“Treatment of H1299 p53c and p53b cells with the NQO1 inhibitor dicuomarol (Figure 5) resulted in a dose dependent degradation of p53c but not p53b, suggesting that NQO1 may be an important enzyme in proteasomal processing of p53c.”
BackgroundInfluentialTuning the proteasome to brighten the end of the journey
Mayor, T., Sharon, M., & Glickman, M. H. (2016) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00198.2016 · Cited by 32
“However, the recent identification of two related proteins that coordinate the 20S proteasome function, NQO1 (5, 90) and DJ-1 (89), has begun to reveal some details on the regulatory principles of this degradation system.”
BackgroundInfluentialJamieson, D., Cresti, N., Bray, J., Sludden, J., Griffin, M. J., Hawsawi, N. M., Famie, E., Mould, E. V. A., Verrill, M. W., May, F. E. B., et al. (2011) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32834b6918 · Cited by 33
Pakay, J. L., Diesch, J., Gilan, O., Yip, Y.-Y., Sayan, E., Kölch, W., Mariadason, J. M., Hannan, R. D., Tulchinsky, E. M., & Dhillon, A. S. (2011) · Oncogene · doi:10.1038/onc.2011.375 · Cited by 32
Natural Small Molecules as Stabilizers and Activators of Cancer-Associated NQO1 Polymorphisms
Pey, A. L., Megarity, C. F., Medina‐Carmona, E., & Timson, D. J. (2016) · Current Drug Targets · doi:10.2174/1389450117666160101121610 · Cited by 30
“such as dicoumarol, other coumarins, flavones and curcumin, antagonise these interactions (38-43).”
BackgroundFang, Q., Andrews, J., Sharma, N., Wilk, A. M., Clark, J., Slyšková, J., Koczor, C. A., Lans, H., Prakash, A., & Sobol, R. W. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz293 · Cited by 30
“Together, these data suggest that NQO1 mediates ubiquitin-independent degradation of Pol in an NADH-dependent manner.”
BackgroundMethodInfluentialTrash Talk: Mammalian Proteasome Regulation at the Transcriptional Level
Kaya, H. E. K., & Radhakrishnan, S. K. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.09.005 · Cited by 32
“Of note, 20S proteasomes are ubiquitin- and proteasome activator- independent complexes and have been found to degrade ~20% of cellular proteins including oxidized forms [71-73].”
BackgroundBenosman, S., Meng, X., von Grabowiecki, Y., Palamiuc, L., Hriţcu, L., Groß, I., Mellitzer, G., Taya, Y., Loeffler, J., & Gaiddon, C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.261271 · Cited by 39
Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
Adam, K., Lambert, M., Lestang, E., Champenois, G., Dusanter‐Fourt, I., Tamburini, J., Bouscary, D., Lacombe, C., Zermati, Y., & Mayeux, P. (2015) · Bioscience Reports · doi:10.1042/bsr20150217 · Cited by 31
Lienhart, W., Strandback, E., Gudipati, V., Koch, K., Binter, A., Uhl, M. K., Rantasa, D. M., Bourgeois, B. M. R., Madl, T., Zangger, K., et al. (2017) · FEBS Journal · doi:10.1111/febs.14051 · Cited by 31
“This effect appears to be related to the interaction of NQO1 with the 20S proteasome in a NADH-dependent manner [3,4].”
BackgroundNQO1 regulates cell cycle progression at the G2/M phase
Oh, E., Kim, H. G., Kim, C. H., Lee, J., Kim, C., Lee, J., Cho, Y., & Park, H. J. (2023) · Theranostics · doi:10.7150/thno.77444 · Cited by 30
“In this context, NQO1 stabilizes several proteins, including CEBPα, p53, p73 and p33ING1b, by blocking their proteasomal degradation [34-38, 40].”
Claveria‐Gimeno, R., Velázquez‐Campoy, A., & Pey, A. L. (2017) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2017.10.020 · Cited by 30
Pacheco‐García, J. L., Anoz‐Carbonell, E., Vaňková, P., Kannan, A., Palomino‐Morales, R., Mesa‐Torres, N., SALIDO, E. C., Man, P., Medina, M., Naganathan, A. N., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102112 · Cited by 28
“step in the reductive half-reaction of NQO1 [22,24], and this state with the flavin reduced is associated with binding to microtubules and α-tubulin acetylation [9], and more generally, it promotes the interaction of NQO1 with protein partners [16,18].”
BackgroundProkaryotic Proteasomes: Nanocompartments of Degradation
Humbard, M. A., & Maupin-furlow, J. A. (2013) · Microbial Physiology · doi:10.1159/000351348 · Cited by 30
“In eukaryotic systems, proteins are targeted for degradation by the proteasome through a variety of mechanisms [Asher et al., 2005; Baugh et al., 2009].”
BackgroundJamart, C., Gomes, A. V., Dewey, S., Deldicque, L., Raymackers, J., & Francaux, M. (2014) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-15-166 · Cited by 30
Overexpression of Annexin A2 Is Associated with Abnormal Ubiquitination in Breast Cancer
Deng, S., Jing, B., Xing, T., Hou, L., & Yang, Z. (2012) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2011.12.001 · Cited by 30
Hyun, D. H., Kim, J., Moon, C., Lim, C. J., de Cabo, R., & Mattson, M. P. (2011) · AGE · doi:10.1007/s11357-011-9245-1 · Cited by 30
“NQO1 is also responsible for the stabilization of proteins degraded by the 20S proteasome (Alard et al. 2010; Asher et al. 2005).”
Vaňková, P., SALIDO, E. C., Timson, D. J., Man, P., & Pey, A. L. (2019) · Biomolecules · doi:10.3390/biom9110728 · Cited by 29
“These protein:protein interactions presumably depend on the functional state of NQO1: binding of NADH may increase the strength of these interactions, while dicoumarol binding has the opposite effect [9,17,19].”
BackgroundNQO1 Stabilizes p53 in Response to Oncogene-Induced Senescence
Liu, K., Jin, B., Wu, C., Yang, J., Zhan, X., Wang, L., Shen, X., Chen, J., Chen, H., & Mao, Z. (2015) · International Journal of Biological Sciences · doi:10.7150/ijbs.11978 · Cited by 28
“Previous reports using various cancer cell lines have indicated that NQO1 binds to p53 [15, 16].”
BackgroundInsights into the Conserved Regulatory Mechanisms of Human and Yeast Aging
Dahiya, R., Mohammad, T., Alajmi, M. F., Rehman, M. T., Hasan, G. M., Hussain, A., & Hassan, M. I. (2020) · Biomolecules · doi:10.3390/biom10060882 · Cited by 30
“ubiquitin-independent proteasomal degradation through its association with the 20S proteasome [170] and it acts as a gatekeeper to regulate the stability of several intrinsically disordered proteins (IDPs)—for instance, p53, p73, and PGC1α—in an NADH-dependent manner [171].”
BackgroundConcept and application of circulating proteasomes
Choi, W. H., Kim, S., Park, S., & Lee, M. J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00692-x · Cited by 31
Actin Cytoskeleton Remodeling by the Alternatively Spliced Isoform of PDLIM4/RIL Protein
Guryanova, O. A., Drazba, J. A., Frolova, E. I., & Chumakov, P. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.241554 · Cited by 27
Muñoz, I. G., Morel, B., Medina‐Carmona, E., & Pey, A. L. (2017) · FEBS Letters · doi:10.1002/1873-3468.12772 · Cited by 26
NQO1 Binds and Supports SIRT1 Function
Tsvetkov, P., Adler, J., Strobelt, R., Adamovich, Y., Asher, G., Reuven, N. B., & Shaul, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.671929 · Cited by 26
Self-citationWillermain, F., JANSSENS, S., Arsenijevic, T., PIENS, I., Bolaky, N., Caspers, L. E., Perret, J., & Delporte, C. (2014) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2014.1791 · Cited by 26
“Therefore, AQP4 is likely to be degraded in a ubiquitin-independent manner by the proteasome as described for other proteins, such as ornitine decarboxylase, p53, p21 Cip , steroid receptor coactivator, p300 or nuclear factor of activated T cells 5 (NFAT5) (44-49).”
Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis
Tozluoǧlu, M., Karaca, E., Haliloǧlu, T., & Nussinov, R. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn481 · Cited by 26
“[D17] NQO1 binds to SAM domain of p73 in a NADH-mediated manner (116).”
BackgroundIdentification of a host cell target for the thiazolide class of broad-spectrum anti-parasitic drugs
Müller, J., & Hemphill, A. F. (2011) · Experimental Parasitology · doi:10.1016/j.exppara.2011.02.007 · Cited by 26
Regulation of the 20S Proteasome by a Novel Family of Inhibitory Proteins
Olshina, M. A., Arkind, G., Deshmukh, F. K., Fainer, I., Taranavsky, M., Hayat, D., Ben‐Dor, S., Ben‐Nissan, G., & Sharon, M. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7816 · Cited by 26
“While the presence of a regulatory mechanism to control this degradation process is highly likely, to date only two 20S proteasome regulators have been identified; NAD(P)H dehydrogenase [quinone] 1 (NQO1) (2, 48) and DJ-1 (47).”
The promiscuity of ARF interactions with the proteasome
Pollice, A., Vivo, M., & Mantia, G. L. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.09.026 · Cited by 28
Roles of the two distinct proteasome pathways in hepatitis C virus infection
Shoji, I. (2012) · World Journal of Virology · doi:10.5501/wjv.v1.i2.44 · Cited by 25
A Functional NQO1 609C>T Polymorphism and Risk of Gastrointestinal Cancers: A Meta-Analysis
Yu, H., Liu, H., Wang, L., & Wei, Q. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030566 · Cited by 25
Metadata
- Authors
- Asher, G., Tsvetkov, P., Kahana, C., & Shaul, Y.
- Affiliations
- Weizmann Institute of Science (IL)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2005-02-01
- Volume
- 19
- Issue
- 3
- Pages
- 316-321
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC546509
- OpenAlex
- W2099952208
- Cited by
- 367
- References
- 24
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 23 · 2020: 17 · 2019: 21 · 2018: 16 · 2017: 26 · 2016: 15 · 2015: 13 · 2014: 23 · 2013: 11 · 2012: 18
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Academy of Sciences and Humanities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, p73, 20S proteasome, NQO1, NADH, tumor suppressor degradation, ionizing radiation response, protein degradation regulation
- MeSH terms
- Tumor Protein p73, Animals, Coenzymes, DNA-Binding Proteins, Humans, Nuclear Proteins, Protein Binding, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, NAD(P)H Dehydrogenase (Quinone), Tumor Suppressor Proteins, Ubiquitin, Protein Interaction Mapping, Proteasome Endopeptidase Complex
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