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RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA, State Key Laboratory for Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China, You can also search for this author in Cyclin F functions in G2 phase to restrict the activity of E2F, the synthesis of replicative histones (SLBP), and the levels of ribonucleotides (RRM2), as well as regulate centrosomal duplication (CP110). 21, 483492 (2002). Cell cycle progression is a tightly regulated process by which DNA replicates and cell reproduces. Google Scholar. The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. 3). Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression. The protein abundance of CDKs is constant, while their activities fluctuate throughout the cell cycle, which is mainly achieved by the periodic expression of cyclin coactivators and CDK inhibitors (CKIs). Two important types of E3 ligases, the anaphase-promoting complex or cyclosome (APC/C) and Skp1-Cul1-F-box (SCF) complexes, are dedicated to cell cycle control. Trends Cell Biol. 14, 4854 (2004). Unidirectional progression through the cell cycle depends on the specific, rapid, and temporally controlled proteolysis of key cellular regulators by the ubiquitin-proteasome system (UPS). At the end of the G1 phase, the accumulation of Cyclin E activates CDK2 and promotes full phosphorylation of RB1 [2, 3], initiating cell cycle transition from G1 phase to S phase. Ras activity regulates cyclin E degradation by the Fbw7 pathway. 10, 19841991 (2004). The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Uckelmann M, Sixma TK. Regarding the role of SCF E3 complex in cancer development, emerging evidence suggest that it acts in a F-box protein- and context-dependent manner [107109]. official website and that any information you provide is encrypted https://doi.org/10.1126/scisignal.2002187. Nature. Jaspersen, S. L., Charles, J. F. & Morgan, D. O. Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. A portion of a protein that is necessary and sufficient to bring about its degradation by the ubiquitinproteasome system. Saigusa, K. et al. Systematic analysis and nomenclature of mammalian F-box proteins.
Ubiquitin ligases: Cell-cycle control and cancer CAS Google Scholar. Fukushima H, Ogura K, Wan L, Lu Y, Li V, Gao D, et al. DAngiolella V, Donato V, Vijayakumar S, Saraf A, Florens L, Washburn MP, et al. Cyclin E-CDK2 is a regulator of p27Kip1. https://doi.org/10.15252/embj.2018101443. The variety of different modifications confers the diversity of linkage-dependent function of ubiquitination. 10, 567572 (2004). Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Briefly, mitotic phosphorylation of APC1 relieves its auto-inhibition and promotes APC/C activation by facilitating CDC20 engagement [33, 34]. Zheng ZM, Wang YY, Chen M, Yang HL, Lai ZZ, Li MQ, Shao J. Int J Med Sci. Not only does ubiquitin-mediated proteolysis constitute a critical component of the core oscillator that drives the cell cycle in all eukaryotes, it is also central to the mechanisms that ensure that the integrity of the genome is maintained. Multi kinase phosphorylation of the APC/C activator Cdh1 revealed by mass spectrometry. Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Chem. Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, et al.
Ubiquitin ligases: cell-cycle control and cancer - Nature The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, et al. Wasch, R. & Engelbert, D. Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Nat Cell Biol. Ras activity regulates cyclin E degradation by the Fbw7 pathway. & Ohama, K. Skp2 overexpression is a prognostic factor in patients with ovarian adenocarcinoma. As mentioned above, Cyclin A association with CDK2, in replace of Cyclin E, is involved in the regulation of the initiation of DNA synthesis when cells enter S phase [4, 5]. Abstract. Cell 93, 10431053 (1998). Seki, R. et al. Nature 349, 132138 (1991). 98, 124128 (2005). Skaar JR, Pagan JK, Pagano M. Mechanisms and function of substrate recruitment by F-box proteins. Garca-Higuera I, Manchado E, Dubus P, Caamero M, Mndez J, Moreno S, et al. 18, 25732580 (2004). 16, 323333 (2005). In addition, degradation of Cyclin B1 inactivates CDK1, preventing APC/C-CDC20 combination while releasing its inhibitory phosphorylation of CDH1 [37]. 2011;25:86374. Then, E2 ubiquitin-conjugating enzymes catalyze the transfer of the ubiquitin from E1 to the active site cysteine of E2. Sutterluty, H. et al. Genes Dev. Prognostic significance of the F-box protein Skp2 expression in diffuse large B-cell lymphoma. Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Altogether, these findings demonstrate that the cell cycle progression is predominantly regulated by the ubiquitinproteasome system [17, 18]. 2022 Oct 11;34:100839. doi: 10.1016/j.neo.2022.100839. Activation of CDH1 thenmediates a large number of mitotic and G1 regulators for ubiquitination and proteasomal degradation, such as Cyclin B1, PLK1, CDC20, FOXM1, and SKP2, facilitating irreversible mitotic exit and G1 maintenance [40]. Nature. 2). Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M, Alessi DR. Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. Natl Acad. Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and -TrCP: tipping the scales of cancer. & Pagano, M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. J. Mammary Gland Biol. The ubiquitin-proteasome system plays a pivotal role in the sequence of events leading to cell division known as the cell cycle. The M checkpoint is also known as spindle assembly checkpoint (SAC), by which cells assess whether all chromosomes are properly attached to the spindle. 116, 42614262 (2003). To obtain FBXO17 Inhibits the Wnt/-Catenin Pathway and Proliferation of Ishikawa Cells. Our results indicate that LRR-1 acts as a nuclear substrate-recognition subunit of a Cullin 2-RING E3 ligase complex . In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cel 2021 Feb; 28(2): 427438. The stages of the cell cycle are divided into four major phases: (1) G1 phase, also called the first gap phase. The recognition of ubiquitinated proteins by the proteasome. Cancer Drug Targets 3, 4155 (2003). The SCF complex and APC/C are structurally similar. 8, 34193426 (2002). Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Mol Cell. Clin. 2). Int. Cangi MG, Cukor B, Soung P, Signoretti S, Moreira G Jr, Ranashinge M, et al. and JavaScript. Clin. Early growth response-1 is a new substrate of the GSK3-FBXW7 axis. Annu Rev Biochem. Clin. Mol. Am. 2002;519:5965. J. Biol. Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplication. 170, 241245 (2003). Sci. Gallahan, D. & Callahan, R. The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oral Oncol. 2016;26:48498. Oncol. In eukaryotic cells, two families of E3 ubiquitin ligases, anaphase-promoting complex/cyclosome and Skp1-Cul1-F-box protein complex, are responsible for ubiquitination and proteasomal degradation of many of these CDK regulators, ensuring cell cycle progresses in a timely and precisely regulated manner. Unable to load your collection due to an error, Unable to load your delegates due to an error. Cell 5, 877882 (2000). Virchows Arch. Singleton MR, Uhlmann F. Separase-securin complex: a cunning way to control chromosome segregation. PubMed The authors wish to thank all members of our laboratories for their comments. Systematic analysis and nomenclature of mammalian F-box proteins. Cancer Lett. Proc Natl Acad Sci USA. Nat Commun. sharing sensitive information, make sure youre on a federal Careers. Targeted disruption of Skp2 results in accumulation of cyclin E and p27. Inverse relationship between Skp2 ubiquitin ligase and the cyclin dependent kinase inhibitor p27Kip1 in prostate cancer. Thank you for visiting nature.com. 2005 Jun;16(3):323-33. doi: 10.1016/j.semcdb.2005.02.010. Cyclin F contains three separate modules, the pseudo-catalytic, substrate recruitment, and regulatory modules. 2017;56:92101. Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. eCollection 2022. On the other hand, TrCP was found to be involved in mediating the proteasomal degradation of tumor suppressors, such as FOXO3 and DEPTOR [119, 120]. Unlike TrCP and FBXW7, SKP2-dependent ubiquitination and degradation of CKIs, such as p27, requires not only the CDK-mediated phosphorylation, but also an accessory protein, CKS1, representing a cofactor-dependent substrate recognition [4850, 99]. 1997;272:1273846. CDH1-deficient cells proliferate inefficiently and CDH1 heterozygous animals show increased susceptibility to spontaneous tumors, largely conferring CDH1 a tumor suppressor role [106].
The ubiquitin proteasome system Implications for cell cycle control High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. You are using a browser version with limited support for CSS. 2022 Sep 14;9:977122. doi: 10.3389/fmolb.2022.977122. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Ubiquitin ligases coordinate the cell cycle and DNA damage repair to maintain genome integrity. Cdc34 C-terminal tail phosphorylation regulates Skp1/cullin/F-box (SCF)-mediated ubiquitination and cell cycle progression. 157, 11251137 (2002). Oncogene. Targets of SKP2 are mainly tumor suppressor proteins including p21, p27, p57, p130, and CDT1 [50,51,52, 111, 112]. & Miyakawa, I. Polo-like kinases (Plks) and cancer. Mol. Revealing -TrCP activity dynamics in livecells with a genetically encoded biosensor, A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer, Identification of the key exosomal lncRNAs/mRNAs in the serum during distraction osteogenesis, Stabilization of CDK6 by ribosomal protein uS7, a target protein of the natural product fucoxanthinol, Targeting the untargetable: RB1-deficient tumours are vulnerable to Skp2 ubiquitin ligase inhibition. Targeting the ubiquitin system in cancer therapy. In addition to the fluctuating accumulation of cyclin activators, two families of CKIs, namely INK4 and CIP/KIP, also contribute to the periodic activation of CDKs over the course of the cell cycle. Lara-Gonzalez P, Westhorpe FG, Taylor SS. Histol. Mol Biol Cell. Open Access Four F-box proteins of SCF E3 ligasecomplex have been well-documented to function in regulation of the cell cycle progression: FBXW7, TrCP, SKP2, and Cyclin F. FBXW7 functions largely as a tumor suppressor to mediate the protein destruction of MYC and Cyclin E. By contrast, SKP2 is believed to serve as an oncogene, which mediates the ubiquitination and degradation of CDK inhibitors, such as p21, p27, and p57. The best-studied degron in targets of APC/C are the nine-amino acid destruction box (D-box: RxxLxxxxN) and the KEN box (KENxxxN), which are preferred by CDH1 and CDC20 or CDH1, respectively [13, 91] (Table1). Meanwhile, the activated Cyclin E-CDK2 complex mediates phosphorylation and ubiquitination of p27 [48, 49]. Chem. Zhang, H., Kobayashi, R., Galaktionov, K. & Beach, D. p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell Dev. 2004;428:1948. We know that CDC20 functions as an upstream adapter protein for Cyclin A, Cyclin B, and Securin, mediating their ubiquitination and proteasomal degradation during mitosis. Here, we show that the leucine-rich repeat protein LRR-1 promotes cell cycle progression during C. elegans development, both in the germ line and in the early embryo. Biol. Visintin, R. et al. A novel ER-microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression. The first paper describing ubiquitylation of p27. It also shows that p27 inhibits CDK1 as well as CDK2. Thus, a better understanding of the diversity and complexity of ubiquitin signaling in cell cycle regulation will shed new light on the precise control of the cell cycle progression and guide anticancer drug development. Serving as an example, CDK2 phosphorylation of the TPPxS of Cyclin E determines its recognition and ubiquitination by FBXW7 [97, 98]. 65, 13161324 (2005). K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M. Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. The abundance of Cyclin B accumulates in M phase, resulting in Cyclin B-CDK1 complex activation and mitosis progression [9,10,11]. A. Skp2 and p27kip1 expression in melanocytic nevi and melanoma: an inverse relationship. J. Pathol. Cell. Genomic stability and tumour suppression by the APC/C cofactor Cdh1. We are also thankful to A. Ohta and M. Kimura for help in preparing this manuscript. Tsunematsu, R. et al. Cell 82, 915925. Rajagopalan, H. et al. CDK inhibitors: positive and negative regulators of G1-phase progression. Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr. Front Oncol. Therefore, a better understanding of the ubiquitin signaling in cell cycle control will expand and diversify the range of anticancer strategies and benefit the clinical treatment of cancer patients in the future. Biol. 18, 26022607 (2004). References 15 and 16 show the interplay between the SCF complex and APC/C through the degradation of SKP2 by APC/CCDH1. Nature. 2013;49:1159-66. Sequential activation of cyclin-dependent kinases (CDKs) drives cell cycle progression in a timely and precisely regulated manner. SCF-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. 2003;17:306274. Ubiquitination is an enzyme-mediated posttranslational modification by which the ubiquitin protein is attached to a substrate protein. Gynecol. Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG Jr. Zhu, C. Q. et al. Genes Chromosomes Cancer 34, 916 (2002). ISSN 1474-175X (print). In addition to the fluctuating accumulation of cyclin activators, two families of CKIs, namely INK4 and CIP/KIP, also contribute to the periodic activation of CDKs over the course of the cell cycle. Cell cycle elongation impairs proliferation of cerebellar granule cell precursors in . 2005;102:964954. Cheng Y, Li G. Role of the ubiquitin ligase Fbw7 in cancer progression. Cell Division 20%. Nature 391, 493496 (1998). J Lipid Res. 2013;201:101326. Kotoshiba, S., Kamura, T., Hara, T., Ishida, N. & Nakayama, K. I. Molecular dissection of the interaction between p27 and Kip1 ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase. 24, 81848194 (2004). Fry, A. M. The Nek2 protein kinase: a novel regulator of centrosome structure. Efficient terminal erythroid differentiation requires the APC/C cofactor Cdh1 to limit replicative stress in erythroblasts. M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCF, Peschiaroli A, Dorrello NV, Guardavaccaro D, Venere M, Halazonetis T, Sherman NE, et al. Proc. Cell. The ubiquitin-proteasome system plays a pivotal role in the sequence of events leading to cell division known as the cell cycle. Cheng Y, Li G. Role of the ubiquitin ligase Fbw7 in cancer progression. Given the importance of the CIP/KIP family of CKIs in regulating cell cycle transition [12, 53], it is conceivable that the disruption of SKP2 E3 ligase activity would cause dysregulation of cell cycle progression. Biochem J. There are eight amino acids (the N-terminal methionine M1 and seven lysine residues: K6, K11, K27, K29, K33, K48, and K63) that can serve as docking points for additional ubiquitin addition. Associations among -TrCP, an E3 ubiquitin ligase receptor, -catenin, and NF-B in colorectal cancer. Shintani, S. et al. Fukuchi, M. et al. G0 phase is a quiescent stage that occurs outside of the cell cycle. Based upon this notion, targeting the E3 ubiquitin ligases involved in cell cycle regulation is expected to provide novel therapeutic strategies for cancer treatment. Proc. 9, 14201426 (2003). APC/C and SCF E3 ligases serve as the two important types of E3 enzymes to regulate the cell cycle progression. How those ubiquitination signaling events at the spindle checkpoint are integrated and orchestrated in a spacetime-dependent manner remains not fully understood. Biol. Regulation of cell cycle progression and gene expression by H2A deubiquitination. Clin. Minella AC, Welcker M, Clurman BE. Article Kossatz, U. et al. Proc Natl Acad Sci USA. 160, 14571466 (2002). UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme. Fiore BD, Davey NE, Hagting A, Izawa D, Mansfeld J, Gibson TJ, et al. Increased expression of the E3-ubiquitin ligase receptor subunit TRCP1 relates to constitutive nuclear factor-B activation and chemoresistance in pancreatic carcinoma cells. USA 102, 62796284 (2005). Simultaneously, CDC14 is released and activated with the onset of anaphase, dephosphorylating and activating the APC/CCDH1 E3 ligase [38, 39]. J. Biol. Upon DNA damage, activation of ATR phosphorylates and activates CHK1 protein kinase, which then mediates phosphorylation and proteasomal degradation of CDC25A in a SCFTrCP-dependent manner [82, 83]. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. Targeting the anaphase promoting complex: common pathways for viral infection and cancer therapy. Control of chromosome stability by the -TrCP-REST-Mad2 axis. Targeting the anaphase promoting complex: common pathways for viral infection and cancer therapy. Given the importance of the CIP/KIP family of CKIs in regulating cell cycle transition [12, 53], it is conceivable that the disruption of SKP2 E3 ligase activity would cause dysregulation of cell cycle progression. McGarry, T. J. https://doi.org/10.1038/s41418-020-00648-0, DOI: https://doi.org/10.1038/s41418-020-00648-0. Nature 400, 3742 (1999). When cells entry into G2 phase, Cyclin F ubiquitinates and restricts the activity of E2Fs, the main and most critical transcriptional engines of the cell cycle [55, 56]; mediates degradation of SLBP to limit H2A.X accumulation and apoptosis upon genotoxic stress [57]; controls genome integrity and centrosome homeostasis by degrading Ribonucleotide Reductase M2 (RRM2) and CP110, respectively [58, 59]. ISSN 1350-9047 (print), Ubiquitin signaling in cell cycle control and tumorigenesis, https://doi.org/10.1038/s41418-020-00648-0, CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses, Highly accurate protein structure prediction with AlphaFold, Chemically stable fluorescent proteins for advanced microscopy, Histone H3 proline 16 hydroxylation regulates mammalian gene expression, A nascent peptide code for translational control of mRNA stability in human cells, Prime editing for precise and highly versatile genome manipulation, Probing the dynamic RNA structurome and its functions, Medin co-aggregates with vascular amyloid- in Alzheimers disease. Mitosis progression [ 9,10,11 ] repair to maintain genome integrity cyclin F contains three separate modules, activated!, Kaelin WG Jr. Front Oncol regulates cell cycle due to an error, unable to load your collection to. 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