Protein Degradation in Cell Cycle

Abstract

Cell cycle is a series of events that take place within a cell, leading to its division and duplication. Protein degradation through ubiquitin‐mediated proteolysis plays an important role in the cell‐cycle regulation. Most importantly, the Anaphase Promoting Complex/Cyclosome (APC/C) and the Skp1‐Cullin‐1‐F‐box complex (SCF) are the two major E3 ubiquitin ligase complexes that regulate proper cell cycle transitions by timely degrading the various key cell cycle regulators. The SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and Wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B, Securin and many other substrates. The APC complex also plays an integral role in the maintenance of chromatin metabolism, particularly in G1 and G0 via destruction of the aurora A kinase. These cell cycle transitions are tightly regulated, and defective regulation of cell cycle leads to genomic instability and ultimately cancer development.

Key Concepts:

  • Cell cycle is an essential physiological process, which generates additional number of cells when the body needs them.

  • Cell cycle checkpoints are the built‐in control mechanisms that ensure the accuracy of cell division in eukaryotic cells.

  • The timely destruction of various cell cycle regulators by the APC/C and the SCF complexes is necessary for proper cell cycle progression.

  • The protein degradation pathways involve the ubiquitin‐mediated modification of substrates, which are subsequently targeted for degradation by the 26S proteasome.

  • Misregulation of the cell cycle processes leads to abnormal cell division, chromosomal instability and subsequently cancer development.

Keywords: ubiquitination; E3 ubiquitin ligase; cell cycle; protein degradation; proteasome; APC; SCF

Figure 1.

Cell cycle regulation by the APC/C and the SCF E3 ubiquitin ligase complexes. SCF ubiquitinates substrates from the late G1 to the early M phase, whereas the APC/C is active from the mid‐M phase (anaphase) to the end of G1 phase. SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B and Securin, as well as many other APC substrates.

Figure 2.

Illustrated mechanism of protein degradation via the ubiquitin‐proteasome pathway. The ubiquitin molecule is activated by the E1 enzyme (ubiquitin activating enzyme). The E2 enzyme, also known as the Ub‐conjugating enzyme, once conjugated to activated ubiquitin, binds one of several ubiquitin ligases (E3) via a structurally conserved binding region. The E3 enzyme, which functions in concert with E2 enzyme, transfers the ubiquitin from the E2 to the substrate proteins. The E3 enzyme determines the substrate specificity of the 3step ubiquitination process. The ubiquitinated substrate protein is ultimately degraded in the 26S proteasome.

Figure 3.

Defects in protein degradation caused by dysfunction of E3 ligases leads to abnormal cell cycle progression and ultimately cancer development. (a) SCFFbw7 degrades the Cyclin E, Myc, Mcl‐1, Jun and Notch oncoproteins. Mutations or dysfunction of Fbw7 leads to stabilisation of cyclinE, c‐Myc and Mcl‐1 that leads to development of various cancers. (b) SCFskp2 degrades the p21, p27 and FOXO1 tumour suppressor proteins. Overexpression of Skp2 is frequently observed in several human cancers including lymphoma, breast and prostate cancer. (c) SCFβ−TRCP degrades key proteins including Ikk, β‐Catenin and REST. In many cancers, β‐TRCP is overexpressed and contributes to increased degradation of Ikk which leads to hyperactivation of NFkB pathway that potentially involved in tumourigenesis. However, in very rare cases, β‐TRCP behaves as a tumour suppressor and deletion or loss of function of β‐TRCP leads to stabilisation of β‐Catenin that contributes to tumourigenesis. (d) On the other hand, APCCdh1 controls the degradation of various cell cycle regulators including Skp2, Cyclin A, Cyclin B, Aurora B, PLK1, Securin and Geminin, most of which function as oncoproteins in vivo. Dysfunction of Cdh1 related to the development of breast, colon, gastric and cervical cancers, and deletion of Cdh1 in mouse predisposes the mice to tumour development.

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References

Adams J (2003) The proteasome: structure, function, and role in the cell. Cancer Treatment Reviews 29(Suppl 1): 3–9.

Bardin AJ and Amon A (2001) Men and sin: what's the difference? Nature Reviews Molecular Cell Biology 2: 815–826.

Bloom J and Cross FR (2007) Multiple levels of cyclin specificity in cell‐cycle control. Nature Reviews Molecular Cell Biology 8: 149–160.

Bloom J and Pagano M (2003) Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Seminars in Cancer Biology 13: 41–47.

Bornstein G, Bloom J, Sitry‐Shevah D et al. (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. Journal of Biological Chemistry 278: 25752–25757.

Burton JL and Solomon MJ (2001) D box and KEN box motifs in budding yeast Hsl1p are required for APC‐mediated degradation and direct binding to Cdc20p and Cdh1p. Genes & Development 15: 2381–2395.

Cohen‐Fix O, Peters JM, Kirschner MW and Koshland D (1996) Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC‐dependent degradation of the anaphase inhibitor Pds1p. Genes & Development 10: 3081–3093.

Cooper G (2000) Chapter 14: The Eukaryotic Cell Cycle. The cell: A Molecular Approach ( 2nd edn), Washington, D.C: ASM Press. ISBN 0‐87893‐87106‐87896.

Dai Y and Grant S (2003) Cyclin‐dependent kinase inhibitors. Current Opinion in Pharmacology 3: 362–370.

Doree M and Galas S (1994) The cyclin‐dependent protein kinases and the control of cell division. FASEB Journal 8: 1114–1121.

Dorrello NV, Peschiaroli A, Guardavaccaro D et al. (2006) S6K1‐ and betaTRCP‐mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314: 467–471.

Frescas D and Pagano M (2008) Deregulated proteolysis by the F‐box proteins SKP2 and beta‐TrCP: tipping the scales of cancer. Nature Reviews Cancer 8: 438–449.

Gao D, Inuzuka H, Tseng A et al. (2009) Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1‐mediated Skp2 destruction. Nature Cell Biology 11: 397–408.

Gerstein AV, Almeida TA, Zhao G et al. (2002) APC/CTNNB1 (beta‐catenin) pathway alterations in human prostate cancers. Genes, Chromosomes and Cancer 34: 9–16.

Guardavaccaro D, Kudo Y, Boulaire J et al. (2003) Control of meiotic and mitotic progression by the F box protein beta‐Trcp1 in vivo. Developmental Cell 4: 799–812.

Harper JW and Adams PD (2001) Cyclin‐dependent kinases. Chemical Reviews 101: 2511–2526.

Hershko DD (2008) Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. Cancer 112: 1415–1424.

Hochegger H, Takeda S and Hunt T (2008) Cyclin‐dependent kinases and cell‐cycle transitions: does one fit all? Nature Reviews Molecular Cell Biology 9: 910–916.

Inuzuka H, Shaik S, Onoyama I et al. (2011) SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471: 104–109.

King RW, Peters JM, Tugendreich S et al. (1995) A 20S complex containing CDC27 and CDC16 catalyzes the mitosis‐specific conjugation of ubiquitin to cyclin B. Cell 81: 279–288.

Li M, Shin YH, Hou L et al. (2008) The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nature Cell Biology 10: 1083–1089.

Mann C and Hilt W (2000) The Ubiquitin‐Proteasome System in Cell Cycle Control. In: Proteasomes: The World of Regulatory Proteolysis. Landers Bioscience, ISBN: 978‐1‐58706‐011‐3.

Morgan D (2007) The Cell Cycle: Principles of Control. 1st edn London: New Science Press. ISBN: 978‐970‐9539181‐9539182‐9539186.

Morgan DO (1997) Cyclin‐dependent kinases: engines, clocks, and microprocessors. Annual Review of Cell and Developmental Biology 13: 261–291.

Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116: 221–234.

Nakayama K, Nagahama H, Minamishima YA et al. (2000) Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO Journal 19: 2069–2081.

Nakayama K, Nagahama H, Minamishima YA et al. (2004) Skp2‐mediated degradation of p27 regulates progression into mitosis. Developmental Cell 6: 661–672.

Nasmyth K (1993) Control of the yeast cell cycle by the Cdc28 protein kinase. Current Opinion in Cell Biology 5: 166–179.

Nigg EA (1995) Cyclin‐dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays 17: 471–480.

Onoyama I, Tsunematsu R, Matsumoto A et al. (2007) Conditional inactivation of Fbxw7 impairs cell‐cycle exit during T cell differentiation and results in lymphomatogenesis. Journal of Experimental Medicine 204: 2875–2888.

Rechsteiner M and Rogers SW (1996) PEST sequences and regulation by proteolysis. Trends in Biochemical Sciences 21: 267–271.

Reimann JD, Freed E, Hsu JY et al. (2001) Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell 105: 645–655.

Saitoh T and Katoh M (2001) Expression profiles of betaTRCP1 and betaTRCP2, and mutation analysis of betaTRCP2 in gastric cancer. International Journal of Oncology 18: 959–964.

Scheffner M, Nuber U and Huibregtse JM (1995) Protein ubiquitination involving an E1‐E2‐E3 enzyme ubiquitin thioester cascade. Nature 373: 81–83.

Skaar JR and Pagano M (2008) Cdh1: a master G0/G1 regulator. Nature Cell Biology 10: 755–757.

Spiegelman VS, Slaga TJ, Pagano M et al. (2000) Wnt/beta‐catenin signaling induces the expression and activity of betaTrCP ubiquitin ligase receptor. Molecular Cell 5: 877–882.

Spiegelman VS, Tang W, Chan AM et al. (2002) Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling. Journal of Biological Chemistry 277: 36624–36630.

Spruck CH, Won KA and Reed SI (1999) Deregulated cyclin E induces chromosome instability. Nature 401: 297–300.

Tedesco D, Lukas J and Reed SI (2002) The pRb‐related protein p130 is regulated by phosphorylation‐dependent proteolysis via the protein‐ubiquitin ligase SCF(Skp2). Genes & Development 16: 2946–2957.

Tetzlaff MT, Yu W, Li M et al. (2004) Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F‐box protein. Proceedings of the National Academy of Sciences of the USA 101: 3338–3345.

Tsunematsu R, Nakayama K, Oike Y et al. (2004) Mouse Fbw7/Sel‐10/Cdc4 is required for notch degradation during vascular development. Journal of Biological Chemistry 279: 9417–9423.

Visintin R, Prinz S and Amon A (1997) CDC20 and CDH1: a family of substrate‐specific activators of APC‐dependent proteolysis. Science 278: 460–463.

Vodermaier HC (2004) APC/C and SCF: controlling each other and the cell cycle. Current Biology 14: R787–R796.

Wasch R, Robbins JA and Cross FR (2010) The emerging role of APC/CCdh1 in controlling differentiation, genomic stability and tumor suppression. Oncogene 29: 1–10.

Welcker M and Clurman BE (2008) FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nature Reviews Cancer 8: 83–93.

Wertz IE, Kusam S, Lam C et al. (2011) Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471: 110–114.

Westbrook TF, Hu G, Ang XL et al. (2008) SCFbeta‐TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452: 370–374.

Zachariae W, Schwab M, Nasmyth K and Seufert W (1998) Control of cyclin ubiquitination by CDK‐regulated binding of Hct1 to the anaphase promoting complex. Science 282: 1721–1724.

Zhang H, Kobayashi R, Galaktionov K and Beach D (1995) p19Skp1 and p45Skp2 are essential elements of the cyclin A‐CDK2 S phase kinase. Cell 82: 915–925.

Further Reading

Ciechanover A (1998) The ubiquitin‐proteasome pathway: on protein death and cell life. EMBO Journal 17: 7151–7160.

Collins K, Jacks T and Pavletich NP (1997) The cell cycle and cancer. Proceedings of the National Academy of Sciences of the USA 94: 2776–2778.

Hershko A and Ciechanover A (1998) The ubiquitin system. Annual Review of Biochemistry 67: 425–479.

Kitagawa K, Kotake Y and Kitagawa M (2009) Ubiquitin‐mediated control of oncogene and tumor suppressor gene products. Cancer Science 100: 1374–1381.

Lipkowitz S and Weissman AM (2011) RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nature Reviews Cancer 11(9): 629–643.

Murata S, Yashiroda H and Tanaka K (2009) Molecular mechanisms of proteasome assembly. Nature Reviews Molecular Cell Biology 10: 104–115.

Nakayama KI and Nakayama K (2006) Ubiquitin ligases: cell‐cycle control and cancer. Nature Reviews Cancer 6: 369–381.

Pesin JA and Orr‐Weaver TL (2008) Regulation of APC/C activators in mitosis and meiosis. Annual Review of Cell and Developmental Biology 24: 475–499.

Vermeulen K, Bockstaele DV and Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferation 36: 131–149.

Wäsch R and Engelbert D (2005) Anaphase‐promoting complex‐dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene 24(1): 1–10.

Wei W, Ayad N G, Wan Y et al. (2004) Degradation of the SCF component Skp2 in cell cycle G1 by the anaphase promoting complex. Nature 428: 194–198.

Yu H (2007) Cdc20: a WD40 activator for a cell cycle degradation machine. Molecular Cell 27(1): 3–16.

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Shaik, Shavali, Liu, Pengda, Fukushima, Hidefumi, Wang, Zhiwei, and Wei, Wenyi(Jun 2012) Protein Degradation in Cell Cycle. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023158]