Cell Cycle: Regulation by Cyclins

Abstract

The cell cycle is defined as the periodic occurrence of events that result in chromosome duplication (deoxyribonucleic acid, DNA replication in S phase) and separation (mitosis). This process is directly regulated by both external stimuli (such as nutrient availability) and internal stimuli (such as cell size and DNA integrity). These events are co‐ordinately driven by the cyclin‐dependent kinases (CDKs). Although the expression of CDKs typically remains relatively constant, their activities are highly regulated by CDK‐binding proteins known as Cyclins. Cyclins are structurally related proteins whose levels fluctuate throughout the cell cycle. Cyclin levels in the cell are dynamically regulated through tight control over both their rate of synthesis and degradation via ubiquitin‐mediated proteolysis. These CDK activators also impart distinct substrate specificity to CDKs for the temporal regulation of cell division.

Key Concepts:

  • Cyclin levels oscillate throughout the cell cycle.

  • Cyclins bind to CDKs and regulate their kinase activity.

  • Cyclin‐CDK complexes direct the specificity of appropriate substrate interactions during the cell cycle.

  • Inappropriate regulation of cyclins can be both the cause and the result of oncogenesis.

  • As well as controlling normal cell cycle progression, cyclins function also in the exiting of the cell cycle (such as G0 in terminally differentiated cells and the onset of senescence caused by DNA damage).

Keywords: cyclin; CDK; cell cycle; CKI; cancer; senescence; substrate specificity

Figure 1.

Cyclin expression and degradation in the yeast and mammalian (human) cell cycle. The combination of both protein level and activity are depicted in the figure. D cyclin expression is induced by mitogenic signals and can be found in the cell during two successive cell cycles under the constant presence of the signal. However, the main role of D cyclins is at the G1/S transition.

Figure 2.

Cyclin B and Cdk1 protein modifications during M and interphase (I). Cdk1 is phosphorylated after binding with cyclin B and the complex is fully activated by dephosphorylation at the Thr14 and Tyr15 residues, resulting in the onset of mitosis. During anaphase, cyclin B is targeted for proteasome‐dependent degradation by the APC, an ubiquitin‐protein ligating enzyme.

Figure 3.

Conservation of the ‘cyclin‐box fold’ among cyclin A, the retinoblastoma protein and the transcription factor TFIIB.

Figure 4.

Structural transformations in CDK during activation and inhibition. CDKs (blue), by themselves, are inactive. Activation occurs through phosphorylation of the T loop (green) and the binding of cyclin (purple) at the PSTAIRE helix (red). These events lead to a conformational change that produces a functional active site (yellow, see text for details). Tertiary inhibitors of the CIP/KIP1 family (p27; orange) block kinase activity by disrupting the N‐terminal domain and penetrating into the catalytic site. Binary inhibitors of the INK family (p19; salmon) distort the CDK N‐terminal domain.

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References

Andrews B and Measday V (1998) The cyclin family of budding yeast: abundant use of a good idea. Trends in Genetics 14: 66–72.

Berardi P, Meyyappan M and Riabowol KT (2003) A novel transcriptional inhibitory element differentially regulates the cyclin D1 gene in senescent cells. Journal of Biological Chemistry 278: 7510–7519.

Brandeis M, Rosewell I, Carrington M et al. (1998) Cyclin B2‐null mice develop normally and are fertile whereas cyclin B1‐null mice die in utero. Proceedings of the National Academy of Sciences of the USA 95: 4344–4349.

Ciemerych MA, Kenney AM, Sicinska E et al. (2002) Development of mice expressing a single D‐type cyclin. Genes & Development 16: 3277–3289.

D'Angiolella V, Donato V, Vijayakumar S et al. (2010) SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature 466: 138–142.

Diehl JA, Yang W, Rimerman RA, Xiao H and Emili A (2003) Hsc70 regulates accumulation of cyclin D1 and cyclin D1‐dependent protein kinase. Molecular and Cellular Biology 23: 1764–1774.

Dulic V, Drullinger LF, Lees E, Reed SI and Stein GH (1993) Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E‐Cdk2 and cyclin D1‐Cdk2 complexes. Proceedings of the National Academy of Sciences of the USA 90: 11034–11038.

Evans T, Rosenthal ET, Youngblom J, Distel D and Hunt T (1983) Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33: 389–396.

Geng Y, Yu Q, Sicinska E et al. (2003) Cyclin E ablation in the mouse. Cell 114: 431–443.

Goda T, Ishii T, Nakajo N, Sagata N and Kobayashi H (2003) The RRASK motif in Xenopus cyclin B2 is required for the substrate recognition of Cdc25C by the cyclin B‐Cdc2 complex. Journal of Biological Chemistry 278: 19032–19037.

Jeffrey PD, Russo AA, Polyak K et al. (1995) Mechanism of CDK activation revealed by the structure of a cyclinA‐CDK2 complex. Nature 376: 313–320.

Kelly BL, Wolfe KG and Roberts JM (1998) Identification of a substrate‐targeting domain in cyclin E necessary for phosphorylation of the retinoblastoma protein. Proceedings of the National Academy of Sciences of the USA 95: 2535–2540.

Kikuchi I, Nakayama Y, Morinaga T, Fukumoto Y and Yamaguchi N (2010) A decrease in cyclin B1 levels leads to polyploidization in DNA damage‐induced senescence. Cell Biol International 34: 645–653.

Koivomagi M, Valk E, Venta R et al. (2011) Dynamics of Cdk1 substrate specificity during the cell cycle. Molecular Cell 42: 610–623.

Masui Y and Markert CL (1971) Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. Journal of Experimental Zoology 177: 129–145.

Miller ME and Cross FR (2001) Cyclin specificity: how many wheels do you need on a unicycle? Journal of Cell Science 114: 1811–1820.

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

Murray AW and Kirschner MW (1989) Cyclin synthesis drives the early embryonic cell cycle. Nature 339: 275–280.

Nurse P (1990) Universal control mechanism regulating onset of M‐phase. Nature 344: 503–508.

Ren S and Rollins BJ (2004) Cyclin C/cdk3 promotes Rb‐dependent G0 exit. Cell 117: 239–251.

Shan J, Zhao W and Gu W (2009) Suppression of cancer cell growth by promoting cyclin D1 degradation. Molecular Cell 36: 469–476.

Susa M, Choy E, Liu X et al. (2010) Cyclin G‐associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. Molecular Cancer Therapeutics 9: 3342–3350.

Swenson KI, Farrell KM and Ruderman JV (1986) The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell 47: 861–870.

Tanenbaum ME, Vallenius T, Geers EF et al. (2010) Cyclin G‐associated kinase promotes microtubule outgrowth from chromosomes during spindle assembly. Chromosoma 119: 415–424.

Townsley FM and Ruderman JV (1998) Proteolytic ratchets that control progression through mitosis. Trends in Cell Biology 8: 238–244.

Verges E, Colomina N, Gari E, Gallego C and Aldea M (2007) Cyclin Cln3 is retained at the ER and released by the J chaperone Ydj1 in late G1 to trigger cell cycle entry. Molecular Cell 26: 649–662.

Wohlschlegel JA, Dwyer BT, Takeda DY and Dutta A (2001) Mutational analysis of the Cy motif from p21 reveals sequence degeneracy and specificity for different cyclin‐dependent kinases. Molecular and Cellular Biology 21: 4868–4874.

Yu DS and Cortez D (2011) A role for CDK9‐cyclin K in maintaining genome integrity. Cell Cycle 10: 28–32.

Further Reading

Barraclough J, Stone A and Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nature Reviews Cancer 11: 558–572.

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

Brown NR, Noble ME, Endicott JA and Johnson LN (1999a) The structural basis for specificity of substrate and recruitment peptides for cyclin‐dependent kinases. Nature cell biology 1: 438.

Brown NR, Noble ME, Lawrie AM et al. (1999b) Effects of phosphorylation of threonine 160 on cyclin‐dependent kinase 2 structure and activity. Journal of Biological Chemistry 274: 8746.

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.

Jackson PK (2008) The hunt for cyclin. Cell 134: 199–202.

Malumbres M and Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nature Reviews Cancer 9: 153–166.

Martin S (2011) Deconstructing the cell cycle. Nature Reviews Molecular Cell Biology 12: 689.

Russo AA, Jeffrey PD, Patten AK, Massague J and Pavletich NP (1996) Crystal structure of the p27kip1 cyclin‐dependent‐kinase inhibitor bound to the cyclin a‐cdk2 complex. Nature 382: 325.

Russo AA, Tong L, Lee JO, Jeffrey PD and Pavletich NP (1998) Structural basis for inhibition of the cyclin‐dependent kinase cdk6 by the tumour suppressor p16ink4a. Nature 395: 237.

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Truman, Andrew W, Kitazono, Ana A, Fitz Gerald, Jonathan N, and Kron, Stephen J(May 2012) Cell Cycle: Regulation by Cyclins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001364.pub3]