Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

N-Terminal-Dependent Protein Degradation and Targeting Cancer Cells

Author(s): Mohamed A. Eldeeb*

Volume 21, Issue 2, 2021

Published on: 18 August, 2020

Page: [231 - 236] Pages: 6

DOI: 10.2174/1871520620666200819112632

Price: $65

Abstract

Intracellular protein degradation is mediated selectively by the Ubiquitin-Proteasome System (UPS) and autophagic-lysosomal system in mammalian cells. Many cellular and physiological processes, such as cell division, cell differentiation, and cellular demise, are fine-tuned via the UPS-mediated protein degradation. Notably, impairment of UPS contributes to human disorders, including cancer and neurodegeneration. The proteasome- dependent N-degron pathways mediate the degradation of proteins through their destabilizing aminoterminal residues. Recent advances unveiled that targeting N-degron proteolytic pathways can aid in sensitizing some cancer cells to chemotherapeutic agents. Furthermore, interestingly, exploiting the N-degron feature, the simplest degradation signal in mammals, and fusing it to a ligand specific for Estrogen-Related Receptor alpha (ERRa) has demonstrated its utility in ERRa knockdown, via N-terminal dependent degradation, and also its efficiency in the inhibition of growth of breast cancer cells. These recent advances uncover the therapeutic implications of targeting and exploiting N-degron proteolytic pathways to curb growth and migration of cancer cells.

Keywords: Cancer cell death, apoptosis, N-degron, N-end rule, protein degradation, proteolysis, ubiquitin, proteasome, PROTACS.

« Previous Next »
Graphical Abstract

[1]
Varshavsky, A. N-degron and C-degron pathways of protein degradation. Proc. Natl. Acad. Sci. USA, 2019, 116(2), 358-366.
[http://dx.doi.org/10.1073/pnas.1816596116] [PMID: 30622213]
[2]
Grumati, P.; Dikic, I. Ubiquitin signaling and autophagy. J. Biol. Chem., 2018, 293(15), 5404-5413.
[http://dx.doi.org/10.1074/jbc.TM117.000117] [PMID: 29187595]
[3]
Eldeeb, M.; Fahlman, R. The-N-end rule: The beginning determines the end. Protein Pept. Lett., 2016, 23(4), 343-348.
[http://dx.doi.org/10.2174/0929866523666160108115809] [PMID: 26743630]
[4]
Varshavsky, A. The ubiquitin system, autophagy, and regulated protein degradation. Annu. Rev. Biochem., 2017, 86, 123-128.
[http://dx.doi.org/10.1146/annurev-biochem-061516-044859] [PMID: 28654326]
[5]
Eldeeb, M.A.; Ragheb, M.A. Post-translational N-terminal arginylation of protein fragments: A pivotal portal to proteolysis. Curr. Protein Pept. Sci., 2018, 19(12), 1214-1223.
[http://dx.doi.org/10.2174/1389203719666180809113122] [PMID: 30091410]
[6]
Eldeeb, M.A.; Siva-Piragasam, R.; Ragheb, M.A.; Esmaili, M.; Salla, M.; Fahlman, R.P. A molecular toolbox for studying protein degradation in mammalian cells. J. Neurochem., 2019, 151(4), 520-533.
[http://dx.doi.org/10.1111/jnc.14838] [PMID: 31357232]
[7]
Eldeeb, M.A.; Ragheb, M.A.; Esmaili, M.; Hussein, F. Physiological state dictates the proteasomal-mediated purging of misfolded protein fragments. Protein Pept. Lett., 2020, 27(3), 251-255.
[http://dx.doi.org/10.2174/0929866526666191026111951] [PMID: 31738130]
[8]
Eldeeb, M.A.; MacDougall, E.J.; Ragheb, M.A.; Fon, E.A.; Beyond, ER Regulating TOM-complex-mediated import by Ubx2. Trends Cell Biol., 2019, 29(9), 687-689.
[http://dx.doi.org/10.1016/j.tcb.2019.07.003] [PMID: 31358413]
[9]
Pohl, C.; Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science, 2019, 366(6467), 818-822.
[http://dx.doi.org/10.1126/science.aax3769] [PMID: 31727826]
[10]
Eldeeb, M.A.; Fahlman, R.P.; Esmaili, M.; Fon, E.A. Formylation of eukaryotic cytoplasmic proteins: Linking stress to degradation. Trends Biochem. Sci., 2019, 44(3), 181-183.
[http://dx.doi.org/10.1016/j.tibs.2018.12.008] [PMID: 30661830]
[11]
Varshavsky, A. Discovery of cellular regulation by protein degradation. J. Biol. Chem., 2008, 283(50), 34469-34489.
[http://dx.doi.org/10.1074/jbc.X800009200] [PMID: 18708349]
[12]
Hershko, A.; Ciechanover, A.; Varshavsky, A. The ubiquitin system. Nat. Med., 2000, 6(10), 1073-1081.
[http://dx.doi.org/10.1038/80384] [PMID: 11017125]
[13]
Varshavsky, A. Regulated protein degradation. Trends Biochem. Sci., 2005, 30(6), 283-286.
[http://dx.doi.org/10.1016/j.tibs.2005.04.005] [PMID: 15950869]
[14]
Hanna, J.; Guerra-Moreno, A.; Ang, J.; Micoogullari, Y. Protein degradation and the pathologic basis of disease. Am. J. Pathol., 2019, 189(1), 94-103.
[http://dx.doi.org/10.1016/j.ajpath.2018.09.004] [PMID: 30312581]
[15]
Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem., 2017, 86(1), 193-224.
[http://dx.doi.org/10.1146/annurev-biochem-061516-044908] [PMID: 28460188]
[16]
Eldeeb, M.A.; Leitao, L.C.A.; Fahlman, R.P. Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation. Biochem. Cell Biol., 2018, 96(3), 289-294.
[http://dx.doi.org/10.1139/bcb-2017-0274] [PMID: 29253354]
[17]
Eldeeb, M.A.; Fahlman, R.P. Phosphorylation impacts N-end rule degradation of the proteolytically activated form of BMX kinase. J. Biol. Chem., 2016, 291(43), 22757-22768.
[http://dx.doi.org/10.1074/jbc.M116.737387] [PMID: 27601470]
[18]
Eldeeb, M.A.; Fahlman, R.P. The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway. Oncotarget, 2014, 5(9), 2714-2722.
[http://dx.doi.org/10.18632/oncotarget.1931] [PMID: 24798867]
[19]
Eldeeb, M.A.; Fahlman, R.P.; Esmaili, M.; Ragheb, M.A. Regulating apoptosis by degradation: The N-end rule-mediated regulation of apoptotic proteolytic fragments in mammalian cells. Int. J. Mol. Sci., 2018, 19(11), 3414.
[http://dx.doi.org/10.3390/ijms19113414] [PMID: 30384441]
[20]
Hou, J.; Eldeeb, M.; Wang, X. Beyond deubiquitylation: Usp30-mediated regulation of mitochondrial homeostasis. In Mitochondrial DNA and Diseases; Sun, H.; Wang, X., Eds.; Springer: Singapore, 2017, Vol. 1038, pp. 133-148.
[http://dx.doi.org/10.1007/978-981-10-6674-0_10]
[21]
Eldeeb, M.A.; Ragheb, M.A.; Esmaili, M. How does protein degradation regulate TOM machinery-dependent mitochondrial import? Curr. Genet., 2020, 66(3), 501-505.
[http://dx.doi.org/10.1007/s00294-020-01056-0] [PMID: 32060627]
[22]
Eldeeb, M.A.; Ragheb, M.A. N-degron-mediated degradation and regulation of mitochondrial PINK1 kinase. Curr. Genet., 2020, 66(4), 693-701.
[http://dx.doi.org/10.1007/s00294-020-01062-2] [PMID: 32157382]
[23]
Bachmair, A.; Finley, D.; Varshavsky, A. In vivo half-life of a protein is a function of its amino-terminal residue. Science, 1986, 234(4773), 179-186.
[http://dx.doi.org/10.1126/science.3018930] [PMID: 3018930]
[24]
Gibbs, D.J.; Bacardit, J.; Bachmair, A.; Holdsworth, M.J. The eukaryotic N-end rule pathway: Conserved mechanisms and diverse functions. Trends Cell Biol., 2014, 24(10), 603-611.
[http://dx.doi.org/10.1016/j.tcb.2014.05.001] [PMID: 24874449]
[25]
Varshavsky, A. The N-end rule pathway and regulation by proteolysis. Protein Sci., 2011, 20(8), 1298-1345.
[http://dx.doi.org/10.1002/pro.666] [PMID: 21633985]
[26]
Tasaki, T.; Sriram, S.M.; Park, K.S.; Kwon, Y.T. The N-end rule pathway. Annu. Rev. Biochem., 2012, 81, 261-289.
[http://dx.doi.org/10.1146/annurev-biochem-051710-093308] [PMID: 22524314]
[27]
Eldeeb, M.A.; Ragheb, M.A.; Fon, E.A. Cell death: N-degrons fine-tune pyroptotic cell demise. Curr. Biol., 2019, 29(12), R588-R591.
[http://dx.doi.org/10.1016/j.cub.2019.05.004] [PMID: 31211982]
[28]
Tasaki, T.; Mulder, L.C.F.; Iwamatsu, A.; Lee, M.J.; Davydov, I.V.; Varshavsky, A.; Muesing, M.; Kwon, Y.T. A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. Mol. Cell. Biol., 2005, 25(16), 7120-7136.
[http://dx.doi.org/10.1128/MCB.25.16.7120-7136.2005] [PMID: 16055722]
[29]
Dissmeyer, N.; Rivas, S.; Graciet, E. Life and death of proteins after protease cleavage: Protein degradation by the N-end rule pathway. New Phytol., 2018, 218(3), 929-935.
[http://dx.doi.org/10.1111/nph.14619] [PMID: 28581033]
[30]
Eldeeb, M.; Esmaili, M.; Fahlman, R. Degradation of proteins with N-terminal glycine. Nat. Struct. Mol. Biol., 2019, 26(9), 761-763.
[http://dx.doi.org/10.1038/s41594-019-0291-1] [PMID: 31477902]
[31]
Eldeeb, M.A.; Fahlman, R.P.; Ragheb, M.A.; Esmaili, M. Does N‐terminal protein acetylation lead to protein degradation? BioEssays, 2019, 41(11)e1800167
[http://dx.doi.org/10.1002/bies.201800167] [PMID: 31549739]
[32]
Hwang, C-S.; Shemorry, A.; Varshavsky, A. N-terminal acetylation of cellular proteins creates specific degradation signals. Science, 2010, 327(5968), 973-977.
[http://dx.doi.org/10.1126/science.1183147] [PMID: 20110468]
[33]
Chen, S-J.; Wu, X.; Wadas, B.; Oh, J-H.; Varshavsky, A. An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes. Science, 2017, 355(6323)eaal3655
[http://dx.doi.org/10.1126/science.aal3655] [PMID: 28126757]
[34]
Timms, R.T.; Zhang, Z.; Rhee, D.Y.; Harper, J.W.; Koren, I.; Elledge, S.J. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science, 2019, 365(6448)eaaw4912
[http://dx.doi.org/10.1126/science.aaw4912] [PMID: 31273098]
[35]
Piatkov, K.I.; Brower, C.S.; Varshavsky, A. The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments. Proc. Natl. Acad. Sci. USA, 2012, 109(27), E1839-E1847.
[http://dx.doi.org/10.1073/pnas.1207786109] [PMID: 22670058]
[36]
Kato, K.; Yamanouchi, D.; Esbona, K.; Kamiya, K.; Zhang, F.; Kent, K.C.; Liu, B. Caspase-mediated protein kinase C-δ cleavage is necessary for apoptosis of vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol., 2009, 297(6), H2253-H2261.
[http://dx.doi.org/10.1152/ajpheart.00274.2009] [PMID: 19837952]
[37]
Lin, Y.; Devin, A.; Rodriguez, Y.; Liu, Z.G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev., 1999, 13(19), 2514-2526.
[http://dx.doi.org/10.1101/gad.13.19.2514] [PMID: 10521396]
[38]
Datta, R.; Kojima, H.; Yoshida, K.; Kufe, D. Caspase-3-mediated cleavage of protein kinase C θ in induction of apoptosis. J. Biol. Chem., 1997, 272(33), 20317-20320.
[http://dx.doi.org/10.1074/jbc.272.33.20317] [PMID: 9252332]
[39]
Kramer, D.A.; Eldeeb, M.A.; Wuest, M.; Mercer, J.; Fahlman, R.P. Proteomic characterization of EL4 lymphoma-derived tumors upon chemotherapy treatment reveals potential roles for lysosomes and caspase-6 during tumor cell death in vivo. Proteomics, 2017, 17(12)1700060
[http://dx.doi.org/10.1002/pmic.201700060] [PMID: 28508578]
[40]
Leboeuf, D.; Abakumova, T.; Prikazchikova, T.; Rhym, L.; Anderson, D.G.; Zatsepin, T.S.; Piatkov, K.I. Downregulation of the Arg/N-degron pathway sensitizes cancer cells to chemotherapy in vivo. Mol. Ther., 2020, 28(4), 1092-1104.
[http://dx.doi.org/10.1016/j.ymthe.2020.01.021] [PMID: 32087767]
[41]
Pore, S.K.; Ganguly, A.; Sau, S.; Godeshala, S.; Kanugula, A.K.; Ummanni, R.; Kotamraju, S.; Banerjee, R. N-end rule pathway inhibitor sensitizes cancer cells to antineoplastic agents by regulating XIAP and RAD21 protein expression. J. Cell. Biochem., 2020, 121(1), 804-815.
[http://dx.doi.org/10.1002/jcb.29326] [PMID: 31407360]
[42]
Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; Mercurio, F.; Crews, C.M.; Deshaies, R.J. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA, 2001, 98(15), 8554-8559.
[http://dx.doi.org/10.1073/pnas.141230798] [PMID: 11438690]
[43]
Winter, G.E.; Buckley, D.L.; Paulk, J.; Roberts, J.M.; Souza, A.; Dhe-Paganon, S.; Bradner, J.E. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science, 2015, 348(6241), 1376-1381.
[http://dx.doi.org/10.1126/science.aab1433] [PMID: 25999370]
[44]
Bondeson, D.P.; Mares, A.; Smith, I.E.D.; Ko, E.; Campos, S.; Miah, A.H.; Mulholland, K.E.; Routly, N.; Buckley, D.L.; Gustafson, J.L.; Zinn, N.; Grandi, P.; Shimamura, S.; Bergamini, G.; Faelth-Savitski, M.; Bantscheff, M.; Cox, C.; Gordon, D.A.; Willard, R.R.; Flanagan, J.J.; Casillas, L.N.; Votta, B.J.; den Besten, W.; Famm, K.; Kruidenier, L.; Carter, P.S.; Harling, J.D.; Churcher, I.; Crews, C.M. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol., 2015, 11(8), 611-617.
[http://dx.doi.org/10.1038/nchembio.1858] [PMID: 26075522]
[45]
Paiva, S-L.; Crews, C.M. Targeted protein degradation: Elements of PROTAC design. Curr. Opin. Chem. Biol., 2019, 50, 111-119.
[http://dx.doi.org/10.1016/j.cbpa.2019.02.022] [PMID: 31004963]
[46]
Zhou, P.; Howley, P.M. Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases. Mol. Cell, 1998, 2(5), 571-580.
[http://dx.doi.org/10.1016/S1097-2765(00)80156-2] [PMID: 9844630]
[47]
Hu, R.; Hochstrasser, M. Recent progress in ubiquitin and ubiquitin-like protein (Ubl) signaling. Cell Res., 2016, 26(4), 389-390.
[http://dx.doi.org/10.1038/cr.2016.43] [PMID: 27033807]
[48]
Shanmugasundaram, K.; Shao, P.; Chen, H.; Campos, B.; McHardy, S.F.; Luo, T.; Rao, H. A modular PROTAC design for target destruction using a degradation signal based on a single amino acid. J. Biol. Chem., 2019, 294(41), 15172-15175.
[http://dx.doi.org/10.1074/jbc.AC119.010790] [PMID: 31511327]
[49]
Wurz, R.P.; Dellamaggiore, K.; Dou, H.; Javier, N.; Lo, M-C.; McCarter, J.D.; Mohl, D.; Sastri, C.; Lipford, J.R.; Cee, V.J.A. “click chemistry platform” for the rapid synthesis of bispecific molecules for inducing protein degradation. J. Med. Chem., 2018, 61(2), 453-461.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01781] [PMID: 28378579]
[50]
Xia, H.; Dufour, C.R.; Giguère, V. ERRα as a bridge between transcription and function: Role in liver metabolism and disease. Front. Endocrinol., 2019, 10(206)
[http://dx.doi.org/10.3389/fendo.2019.00206]
[51]
Kechko, O.I.; Petrushanko, I.Y.; Brower, C.S.; Adzhubei, A.A.; Moskalev, A.A.; Piatkov, K.I.; Mitkevich, V.A.; Makarov, A.A. Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg/N-end rule pathway proteolytic activity. Aging (Albany NY), 2019, 11(16), 6134-6152.
[http://dx.doi.org/10.18632/aging.102177] [PMID: 31446431]
[52]
Varshavsky, A. The N-end rule and regulation of apoptosis. Nat. Cell Biol., 2003, 5(5), 373-376.
[http://dx.doi.org/10.1038/ncb0503-373] [PMID: 12724766]

Rights & Permissions Print Cite
Article Metrics
53
© 2024 Bentham Science Publishers | Privacy Policy