Cell Cycle

Abstract

Competency for proliferation and cell cycle progression are governed by complex and interdependent processes that support DNA replication and mitotic division. Genetic and epigenetic controls are operative. The architectural organisation of the regulatory machinery for gene expression is compartmentalised in microenvironments of interphase nucleus and at gene loci on mitotic chromosomes. The cell cycle requires selective expression of genes that encode cell cycle regulatory proteins. A broad spectrum of signalling mechanisms integrate and amplify growth‐related regulatory cues that mediate fidelity of cell cycle control. There are unique requirements for cell cycle control to support the rapid proliferation that occurs during initial stages of embryogenesis and continued renewal of stem cell populations. The cell cycle regulatory mechanisms that are compromised in cancer cells provide insight into control of transformation and tumourigenesis as well as serve as targets for therapy.

Key Concepts:

  • Competency for proliferation and cell cycle progression requires selective expression of genes that encode cell cycle regulatory proteins.

  • Transcriptional and post‐transcriptional mechanisms mediate control of the cell cycle.

  • Genetic and epigenetic mechanisms support cell cycle progression.

  • The regulatory machinery for gene expression that supports cell cycle control is architecturally organised and assembled in nuclear microenvironments.

  • Unique mechanisms govern control of proliferation during early embryogenesis and for renewal of stem cell populations.

  • Regulatory parameters of cell cycle control that are compromised in cancer cells serve as a platform for tumour diagnosis and therapy.

  • Synchronisation of cell cycle progression supports identification of cell cycle regulatory parameters and mechanisms that are compromised in transformed and tumour cells.

  • Regulatory mechanisms that control the cell cycle in yeast have provided valuable insight into cell cycle control in mammalian cells.

Keywords: cell cycle; histones; cyclins; gene expression; DNA synthesis

Figure 1.

Cell cycle regulation. The four stages of the somatic cell cycle (G1, S, G2 and M) support duplication of the genome and subsequent segregation of a diploid set of chromosomes into two progeny cells. Cells can exit the cell cycle into a quiescent nondividing state (G0) with the option to reenter the cell cycle or to differentiate into a committed cell expressing phenotypic markers characteristic of distinct tissue‐specific lineages (upper panel). Postfertilisation, during early development, embryonic stem (ES) cells derived from the inner cell mass (ICM) of blastocysts have an abbreviated cell cycle. During lineage commitment, cells continue to divide with a normal but extended cell cycle, which supports growth, differentiation and organogenesis. Under pathological circumstances de‐regulation of cell cycle control may lead to cancer or to a proliferative disorder. Tissue‐specific stem cells with an asymmetric division (largely quiescent) enter the cell cycle to support physiological requirements (i.e. tissue remodelling and wound healing). The reprogramming of pre‐committed somatic cells to a pluripotent state result in the reacquisition of a shortened cell cycle with a short G1 phase and constant S, G2 and M phases.

Figure 2.

Multiple checkpoints control cell cycle progression. (a) The cell cycle is regulated by several critical cell cycle checkpoints (ticks) at which competency for cell cycle progression is monitored. Entry into and exit from the cell cycle (black lines and lettering) is controlled by growth regulatory factors (e.g. cytokines, growth factors, cell adhesion and/or cell–cell contact), which determine self‐renewal of stem cells and expansion of pre‐committed progenitor cells. The biochemical parameters associated with each cell cycle checkpoint are indicated by red lettering. Options for defaulting to apoptosis (blue lettering) during G1 and G2 are evaluated by surveillance mechanisms that assess fidelity of structural and regulatory parameters of cell cycle control. (b) Transcription factors (green) are organised in distinct foci in the interphasic nuclei. Although some lineage‐specific transcription factors (i.e. RUNX2) are retained on target gene promoters in chromosomes at all stages of mitosis, others do not associate with chromosomes and are degraded. This retention of transcription factors in addition to the occurrence of certain histone modifications indicate that certain genes are bookmarked for expression after mitosis.

Figure 3.

Surveillance and editing mechanisms mediating checkpoint control. (a) Surveillance mechanisms monitor multiple biochemical and architectural parameters that control cell cycle progression. These parameters include the intracellular levels of regulatory proteins, structural and informational integrity of the genome, as well as extracellular signals governing cell cycle progression. The integration of this regulatory input can result in (i) competency for cell cycle progression (green traffic light and arrows), (ii) cell cycle inhibition and activation of editing mechanisms (yellow traffic light and arrows) or (iii) the active and regulated destruction of the cell in response to apoptotic signals (red traffic light and red arrow). (b) Traverse of the cell cycle is regulated by a series of checkpoints at strategic positions within the cell cycle. Several major checkpoints (yellow arrows with ticks and blue lettering) only allow a cell to commit to a subsequent cell cycle stage upon satisfying essential biochemical and architectural criteria governing competency for cell cycle progression (green traffic lights). For example, at the ‘restriction point’ surveillance mechanisms (yellow traffic lights) integrate cell growth stimulatory and inhibitory signals, including growth factors, cell adhesion and nutrient status (blue lettering). Checkpoints in G1 and G2 are necessary to ensure the integrity of the genome and, if necessary, activate chromatin editing mechanisms (blue lettering). The spindle assembly checkpoint ensures equal chromosome segregation. (c) Checkpoint control mechanisms monitor intracellular levels of cell cycle regulatory factors, as well as parameters of chromatin architecture. For example, the activation of cyclin‐dependent kinases reflects the sensing of intracellular concentrations of the cognate cyclins. CDK activation is attenuated by CDK inhibitor proteins (CKIs) which inactivate CDK/cyclin complexes. Competency for cell cycle progression requires that cyclin levels reach a threshold (e.g. by exceeding the levels of available CKIs, or phosphorylation events altering the affinities of cyclins and CKIs for CDKs). As a consequence, activated CDK/cyclin complexes phosphorylate transcription factors that regulate expression of cell cycle stage‐specific genes. Furthermore, key checkpoints in G1 and G2 monitor chromatin integrity and perform essential editing functions. DNA damage activates DNA‐repair mechanisms that fix informational errors in the genome and restore nucleosomal organisation by chromatin remodelling.

Figure 4.

Regulation of the cell cycle by cyclin‐dependent kinases and tumour suppressor proteins. Competency for cell cycle progression is determined by cyclin‐dependent kinases (CDKs; yellow rounded boxes), which monitor intracellular levels of cyclins (flat red ovals) and CDK inhibitory proteins (CKIs; blue circles). CDKs mediate phosphorylation of the pRB class of tumour suppressor proteins (i.e. pRB/p105, p107 and p130), which results in activation of E2F and CDP/cut‐homeodomain transcription factors (red ovals) as well as the induction of the HINFP/p220NPAT coactivation complex that mediates histone gene expression. These E2F‐dependent and ‐independent mechanisms induce expression of genes required for the G1/S phase transition. The activities of CDKs are also influenced by phosphorylation (e.g. wee1 or CDK‐activating kinase (CAK)), dephosphorylation (CDC25), ubiquitin‐dependent proteolysis and induction of CKIs by the tumour suppressor protein p53. Options for apoptosis are indicated within the context of cell cycle regulatory factors. Growth factors and cytokines induce the activities of CDKs which mediate the G0/G1 transition (red arrow). Vitamin D and TGFb‐dependent cell signalling pathways upregulate CDKIs (e.g. p21 and p27), which block cell cycle progression and supports differentiation in the presence of tissue‐specific regulatory factors.

Figure 5.

Transcriptional control at the G1/S phase transition. The genes encoding cell cycle regulatory subunits (e.g. cyclin E) and histone biosynthesis (e.g. H4) are each controlled by intricate arrays of promoter regulatory elements that influence transcriptional initiation by RNA polymerase II. E2F elements in the promoter of the cyclin E gene interact with E2F factors that associate with CDKs, cyclins and pRB‐related proteins. In contrast, histone genes are controlled by the site II cell cycle regulatory element, which interacts with CDP‐cut and IRF2 proteins, and the HINFP/p220NPAT complex. Analogous to E2F‐dependent mechanisms, CDP‐cut interacts with CDK1, cyclin A and pRB, whereas IRF2 performs an activating function similar to ‘free’ E2F. HINFP binds to this cell cycle regulatory element (site II) and recruits p220NPAT, thus integrating signals from the cyclin E/CDK2 kinase pathway. The presence of SP1 in the promoters of G1/S phase‐related genes provides a shared mechanism for further enhancement of transcription at the onset of S phase.

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References

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Becker KA, Stein JL, Lian JB, van Wijnen AJ and Stein GS (2007) Establishment of histone gene regulation and cell cycle checkpoint control in human embryonic stem cells. Journal of Cellular Physiology 210(2): 517–526.

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Further Reading

Becker KA, Stein JL, Lian JB, van Wijnen AJ and Stein GS (2010) Human embryonic stem cells are pre‐mitotically committed to self‐renewal and acquire a lengthened G1 phase upon lineage programming. Journal of Cellular Physiology 222(1): 103–110.

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Malumbres M, Harloe E, Hunt T et al. (2009) Cyclin‐dependent kinases: a family portrait. Nature Cell Biology 11(11): 1275–1276.

Marzluff WF, Wagner EJ and Duronio RJ (2008) Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nature Reviews Genetics 9(11): 843–854.

Nizami Z, Deryusheva S and Gall JG (2010) The Cajal Body and histone locus body. Cold Spring Harbor Perspectives in Biology 2(7): 1–12.

Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proceedings of the National Academy of Sciences of the USA 71(4): 1286–1290.

Pardee AB (1989) G1 events and regulation of cell proliferation. Science 246: 603–608.

Pardee AB and Stein GS (eds) (2009) The Biology and Treatment of Cancer: Understanding Cancer. Hoboken, NJ: John Wiley & Sons Inc.

Stein GS, van Wijnen A, Stein JL et al. (2010) Control of the human pluripotent cell cycle. In: Bongso A and Lee EH (eds) Stem Cells: From Bench to Bedside, 2nd edn., pp. 235–251 Singapore: World Scientific Press.

Zaidi SK, Young DW, Javed A et al. (2007) Nuclear microenvironments in biological control and cancer. Nature Reviews Cancer 7: 454–463.

Zaidi SK, Young DW, Montecino M et al. (2010) Mitotic bookmarking of genes: a novel dimension to epigenetic control. Nature Reviews Genetics 11(8): 583–589.

Zwaka TP and Thomson JA (2005) Differentiation of human embryonic stem cells occurs through symmetric cell division. Stem Cells 23(2): 146–149.

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Stein, Gary S, Medina, Ricardo, van Wijnen, André J, Stein, Janet L, Lian, Jane B, and Owen, Thomas A(Nov 2011) Cell Cycle. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001354.pub2]