The Cell Cycle




Abstract


The cell cycle is a process in which a cell first duplicates its genetic information and then divides to give rise to two daughter cells. To avoid mis-segregation of the genetic materials and incorporation of errors in the genome, the cell cycle is carefully monitored. This is achieved by positioning throughout the cell cycle a number of checkpoints designed to detect DNA damage, misaligned chromosomes, and incompletely replicated DNA. Checkpoints are mediated by cyclin-dependent kinase inhibitors (CKIs) in interphase and mitosis. On the other hand, progression through the cell cycle requires the combination of cyclins and cyclin-dependent kinases (CDKs), together of which regulate activities of target proteins by phosphorylation. The proper regulation of the cell cycle is critically important for cell proliferation as mutations in genes involved in cell cycle control often lead to cancer. This chapter reviews the components of the cell cycle and its control, checkpoint mechanisms, and provide examples of pathological consequences of dysregulation of the cell cycle machinery. This information is crucial for understanding the mechanisms regulating growth, proliferation, and differentiation of cells in the gastrointestinal tract.




Keywords

Cyclins, Cyclin-dependent kinases (CDKs), CDK inhibitors (CKIs), Checkpoint, Cancer, DNA damage repair, Mitosis, RB, p53, FBXW7, Ubiquitination, Growth factors, Mitogens, Spindle assembly checkpoint (SAC)

 




Acknowledgment


This work was in part supported by grants from the National Institutes of Health (DK052230, DK093680, CA084197, and CA172113).




8.1


Components of the Cell Cycle


A typical eukaryotic cell cycle contains several distinct phases, which progress in an orderly fashion—a phase cannot commence without completion of the previous one. The four phases of the cell cycle are G 1 (G for gap), S (synthesis), G 2 , and M (mitosis) phases ( Fig. 8.1 ). The G 1 , S, and G 2 phases collectively make up the interphase. The DNA content of a cell in the G 1 phase is 2N (N is the number of chromosomes), also known as diploid, whereas the DNA content of a cell in the G 2 phase is 4N (tetraploid). The DNA content of a cell in the S phase varies between 2N and 4N, depending on the stage of replication. The M phase is in turn comprised of two processes: mitosis, in which the cell’s chromosomes are equally divided between the two daughter cells, and cytokinesis (or cell division), in which the cytoplasm of the cell divides in half to form two distinct daughter cells. Typically, the amount of time required for a single-cell cycle in actively proliferating human cells in culture is 24 hours. Of these, the M phase takes approximately 1 hour to complete and interphase takes up the remaining 23 hours.




Fig. 8.1


The phases of the cell cycle. The cell cycle begins in the G 1 phase of a diploid cell (DNA content = 2N; N is the number of chromosomes). After DNA replication is completed in the S phase, the cell enters the G 2 phase and has twice the amount of the DNA (4N) of the starting cell. This is followed by mitosis (M) and cell division, which leads to the formation of two diploid daughter cells. Cells in either mitosis or cell division (also called cytokinesis) are in the M phase, whereas those in the other three phases (G 1 , S, and G 2 ) are in the interphase. The time in which a cell spends in each phase varies among the cell type and is not drawn to scale.


In addition to the four phases of the cell cycle listed above, one phase that lies outside the cell cycle is called the G 0 (0 for zero) phase. Cells in this phase are in the resting phase, which is often the result of their leaving the G 1 phase of the cell cycle. Typically, a cell enters G 0 phase if the environment is not conducive for the progression of the cell cycle, as in the event of deprivation of essential nutrients or growth factors, or if a cell has reached a fully differentiated state such as a hepatocytes or neuron. In these conditions, the cell is sometimes referred to as in a quiescent state. Additionally, a cell can enter the G 0 phase and become senescent due to DNA damage or telomere attrition. This is often an alternative to self-destruction of the damaged cell by apoptosis.


In the M phase, mitosis commences when DNA condenses into visible chromosomes, followed by the separation of the chromosomes into two identical sets. Cytokinesis is the last phase of mitosis when the two daughter cells separate, each with a nucleus and cytoplasmic organelles. Mitosis begins with nuclear membrane breakdown followed by condensation of the chromosomes and separation of the centrosomes (prophase). This is accompanied by the formation of mitotic spindles, which are attached on one end, the centrosomes, and the other end, kinetochore, a protein structure located at or near the centromeres of mitotic chromosomes (prometaphase). At this point, kinetochores that are unattached to the mitotic spindles generate a “wait” signal that delays the onset of anaphase until all chromosomes are properly attached and aligned. This signal is also called mitotic checkpoint or spindle assembly checkpoint (SAC), which is satisfied once all chromosomes are congregated at the equatorial plate (metaphase). This is followed by separation of the chromosomes to the opposite poles (anaphase) and formation of new nuclear membranes around the daughter nuclei and uncoiling of the chromosomes (telophase), eventually forming a cleavage furrow that leads to the formation of two daughter cells (cytokinesis). Fig. 8.2 illustrates the various stages of mitosis.




Fig. 8.2


The stages of mitosis. The different phases of mitosis are illustrated. SAC is spindle assembly checkpoint.

(Adapted from reference Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005;5(10):773–85, with permission from Nature Publishing Group.)




8.2


Control of the Cell Cycle


The organization of the cell cycle and its control system are highly conserved among eukaryotic organisms. Abundant information on how the cell cycle is regulated in vertebrates was derived from earlier studies in yeast. These studies demonstrate that both cell cycle progression and cell division are driven by the sequential activation, and subsequent inactivation, of two key classes of regulatory molecules, cyclins, and cyclin-dependent kinases (CDKs) Cyclins and CDKs form heterodimers with the former acting as the regulatory subunits and the latter catalytic subunits; CDKs are inactive in the absence of their cyclin partners. Specific pairs of cyclin-CDK dimers function in specific phases of the cell cycle ( Fig. 8.3 ). For example, the cyclin E-CDK2 complex becomes active late in the G 1 phase and is responsible for the transition from G 1 into S phase. When activated by a bound cyclin, CDKs phosphorylate a series of downstream target proteins, either activating or inactivating them, which then orchestrate the coordinated entry into the next phase of the cell cycle. The identities of the target proteins depend on the particular combination of cyclin-CDK complexes. While CDKs are constitutively expressed throughout the cell cycle, cyclins are synthesized (and destroyed) in specific stages of the cell cycle (hence the name cyclin), which is often dependent upon various signaling molecules. This cyclic nature of cyclin expression ensures that CDKs are activated and inactivated in a precise manner and safeguards the orderly progression of the cell cycle ( Fig. 8.4 ).




Fig. 8.3


The cell cycle is driven by cyclin-cyclin-dependent (CDK) complexes. The various pairs of cyclin-CDK complexes and their respective positions in the cell cycle are shown in the figure.



Fig. 8.4


Relative expression levels of cyclins in the cell cycle. The relative protein levels of the four different cyclins in various phases of the cell cycle are demonstrated. The letters in parenthesis indicate the classes of cyclins. The levels of cyclin D often fluctuate, depending on whether growth factors or mitogens are present or not. “R” indicates the restriction point.


8.2.1


Cyclins


Cyclins were named because they undergo a cycle of synthesis and degradation in each cell cycle. Depending on the timing of their expression and functions in the cell cycle, cyclins are divided into four classes. Three of these classes, the G 1 /S cyclins, S cyclins, and M cyclins are directly involved in the control of cell cycle events. The fourth class, the G 1 cyclins, controls the entry into the cell cycle in response to extracellular growth factors or mitogens. In the G 1 phase, growth factors are necessary to initiate and maintain the proper transition to the S phase. Early in the G 1 phase, growth factors stimulate the synthesis of G 1 cyclins, represented by the cyclin D family of cyclins, which activates CDK4/6 to induce synthesis of downstream targets, one of which is cyclin E. The rise in cyclin E (a G 1 /S cyclin) levels and activity of its partner, CDK2, drive the cell past a restriction point (R in Fig. 8.4 ) in the cell cycle after which the cell is irreversibly committed to proceeding to DNA synthesis, even if the growth factors are withdrawn. Subsequently, the S cyclins (represented by cyclin A) and M cyclins (represented by cyclin B) are required for the initiation of DNA replication and entry into mitosis, respectively ( Fig. 8.4 ).


8.2.1.1


G 1 Cyclins


The G 1 cyclins are composed of the D-type cyclins that include cyclins D1, D2, and D3. Along with their partners, CDK4 and CDK6, G 1 cyclins act early in the G 1 phase of the cell cycle. The levels of G 1 cyclin are low in G 0 phase and increase progressively upon addition of growth factors or mitogens to the cells. The mechanisms by which mitogens or growth factors activate cyclin D1 are complex and occur at both transcriptional and posttranscriptional levels. At the transcriptional level, induction of cyclin D1 by growth factors is dependent on the RAS/RAF/mitogen- activated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. Once synthesized, cyclin D1 protein has a short half-life —its turnover being governed by ubiquitination and proteasomal degradation, which in turn are dependent on phosphorylation of cyclin D1 by glycogen synthase kinase-3β (GSK-3β). Growth factors prevent cyclin D1 degradation by inhibiting GSK-3β-dependent phosphorylation of cyclin D1 through the Ras/phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. It was subsequently demonstrated that growth factor induced cyclin D1 gene transcription by the MEK/ERK pathway and cyclin D1 protein stabilization by the PI3K/AKT pathway need to occur in a sequential manner with the former occurring early and the latter occurring late in the G 1 phase in order to drive the progression of the cell cycle.


One of the key targets of an activated cyclin D-CDK4/6 complex is the retinoblastoma (RB) protein. RB is one of three “pocket protein” family of cell cycle regulator proteins—the other two being p107 and p130—and has a major role in restraining the transition between G 1 and S phases of the cell cycle. In the absence of mitogenic stimuli, RB interacts with and inhibits the activity of the transcription factor E2F. As E2F-binding sites are present in the promoters of many genes required for cell cycle progression, the inhibition of E2F by RB prevents entry into the cell cycle. In addition to physically interacting with E2F, RB also recruits chromatin remodeling enzymes such as histone deacetylases (HDACs) that often serve as transcription corepressors. Thus, the binding of RB to E2F not only simply inhibits E2F activity, but the RB-E2F complex binds to promoters and actively represses transcription by blocking activity of the surrounding enhancers on the promoter.


The activity of RB is governed by phosphorylation catalyzed by CDKs. RB contains 16 potential phosphorylation sites by CDKs and oscillates between hypophosphorylated and hyperphosphorylated forms during the cell cycle. The form that inhibits E2F is the hypophosphorylated form. CDKs, in complex with their cyclin partners, phosphorylate the hypophosphorylated form of RB, leading to the hyperphosphorylated form. At least three different cyclin-CDK complexes are known to phosphorylate RB during the cell cycle-cyclin D-CDK4/6 acts early in G 1 ; cyclin E-CDK2 in late G 1 ; and cyclin A-CDK2 in the S phase. In this way, RB becomes sequentially phosphorylated in the cell cycle. It has been shown that successive phosphorylation of RB by cyclin D-CDK4/6 and cyclin E-CDK2 is necessary for the complete hyperphosphorylation of RB. The hyperphosphorylation of RB prevents its binding to E2F, thus releasing E2F from transcriptional repression. Once liberated from RB, E2F, along with its partner transcription factor DP, activate transcription of genes that are involved in nucleotide metabolism and DNA synthesis, thus allowing entry into the S phase . It is of interest to note that one of the target genes of an active E2F encodes cyclin E. It was also shown that phosphorylation of RB by cyclin D-CDK4/6 and cyclin E-CDK2 triggers sequential intramolecular interactions in RB that progressively block RB functions as cells move through G 1. The complete hyperphosphorylation of RB by cyclin D-CDK4/6 and cyclin E-CDK2 coincides with the R point ( Fig. 8.4 ), beyond which the cell is committed to completion of the cell cycle.


8.2.1.2


G 1 /S Cyclins


Cyclins E1 and E2 (collectively considered as cyclin E) are the G 1 /S cyclins. Transcription of the cyclin E gene is regulated by E2F, which, as described above, is activated due to cyclin D-CDK4/6-stimulated phosphorylation of RB. The amounts of cyclin E protein and its associated kinase (CDK2) activity are maximal in late G 1 and early S phases ( Fig. 8.4 ). Cyclin E-CDK2 completes RB phosphorylation in the G 1 phase and the transition from cyclin D-CDK4/6 to cyclin E-CDK2 accounts for the loss of dependency on growth factors. Cyclin E-CDK2 phosphorylates RB on different sites from cyclin D-CDK4/6, and these kinases may differentially impact the interaction between RB and E2Fs, HDACs, and other chromatin remodeling proteins. In contrast to cyclin D-CDK4/6, the functions of cyclin E-CDK2 are not limited to G 1 control. Thus, cyclin E-CDK2 phosphorylates other substrates that are more directly involved in the control of DNA replication, centrosome duplication, replication origin licensing and firing. The timing of cyclin E-CDK2 activation and its broader range of substrates suggest that cyclin E-CDK2 spans the interface between G 1 regulation and core cell cycle machinery during S phase.


In early S phase, cyclin E-CDK2 activity abruptly ceases as a consequence of cyclin E degradation ( Fig. 8.4 ). This is mediated by phosphorylation by both GSK-3β and CDK2, which target cyclin E for ubiquitination by the SCF Fbw7 E3 ligase, leading it to proteasomal degradation. Like cyclin D1, the involvement of GSK-3β, an enzyme that is inhibited by the PI3K/AKT signaling pathway, in regulating stability of cyclin E suggests that cyclin E can be influenced at least by one mitogen-dependent signaling cascade.


8.2.1.3


S Cyclins


The S cyclins include both cyclins A1 and A2. While cyclin A1 is restricted to the germ cell lineages, cyclin A2 is ubiquitously expressed in all cell types. Low levels of cyclin A2 are first detected at the G 1 /S boundary. The levels then rise steadily as cells begin to replicate their DNA and do not decline until cyclin A is degraded in late G 2 ( Fig. 8.4 ). In S phase, cyclin A and its partner, CDK2, phosphorylate substrates that commence DNA replication from preformed replication initiation complexes. Cyclin A-CDK2 are also required to coordinate the end of the S phase with activation of the mitotic cyclin-CDKs.


8.2.1.4


M Cyclins


During G 2 , A-type cyclins (the S cyclins) are degraded by ubiquitin-mediated proteolysis whereas B-type cyclins (the M cyclins) are actively synthesized ( Fig. 8.4 ). As a consequence, CDK1 (also known as Cdc2) binds to B-type cyclins—an association required for the commencement of mitosis. CDK1 preferentially binds to two main B-type cyclins, cyclins B1 and B2. In contrast, the third isoforms, cyclin B3, may have a function in the meiotic cell cycle. Cyclin B-CDK1 regulate events during both the G 2 /M transition and progression through mitosis. This is accomplished by the phosphorylation of over 70 proteins by the cyclin B-CDK1 complexes although the number of substrates could be much larger. Phosphorylation of target proteins leads to numerous events that include separation of centrosomes. condensation of chromosomes, breakdown of the nuclear lamina, and disassembly of the Golgi apparatus, among others. Finally, inactivation of the cyclin B-CDK1 complexes is required for proper exit from mitosis and this inactivation is achieved by the degradation of B-type cyclins by ubiquitin-mediated proteolysis that is regulated by the anaphase-promoting complex/cyclosome (APC/C).


8.2.2


Cyclin-Dependent Kinases (CDKs)


CDKs are the catalytic subunits of a relatively large family of serine/threonine protein kinases with a primary role in cell cycle progression. The mammalian genome contains 11 genes encoding CDKs and nine others encoding CDK-like proteins with conserved structure. The prototype CDK, CDK1, was first identified in yeasts and designated as Cdc2 in Saccharomyces pombe or Cdc28 in Saccharomyces cerevisiae . The mammalian homologue of yeast Cdc2, CDK1, was subsequently identified due to its ability to complement the yeast mutants. Other mammalian CDKs were then identified by a host of techniques including complementation, homology probing, differential display, and PCR amplification with degenerate primers. Again, as described above, progression through the G 1 phase of the cell cycle requires at least three CDKs—CDK4, CDK6, and CDK2—which, along with their regulatory cyclins, target the RB family of proteins that include RB, p107, and p130. CDK2 is also important for S phase progression and CDK1 for G 2 /M transition and mitosis.


The kinase activities of CDKs are regulated at multiple levels, including interaction with their regulatory subunits (cyclins), binding to negative regulators called CDK inhibitors or CKIs (see below), phosphorylation-dephosphorylation, folding and subcellular localization. Among these, phosphorylation-dephosphorylation can have activating or inhibitory effects on CDK activity. For example, active cyclin- CDK complexes need to be phosphorylated in the T-loop of the CDK subunit by CDK-activating kinase (CAK), which contains a complex of CDK7, cyclin H, and MAT1 ( Fig. 8.5 ). In contrast, cyclin-CDK complexes can be negatively regulated by phosphorylation in adjacent threonine and tyrosine residues of the CDK subunit by the dual-specificity protein kinases WEE1 and MYT1. Conversely, these inhibitory phosphorylations can be reversed by the ability of the dual-specificity CDC25 phosphatases (CDC25A, CDC25B, and CDC25C) to dephosphorylate the same threonine and tyrosine residues and thus act as positive regulators of cyclin-CDK activity ( Fig. 8.5 ). If both activating and inactivating phosphorylations exist in the same molecule, they result in an inactive kinase.




Fig. 8.5


The regulatory mechanisms of cell cycle CDKs. CDKs require binding to their cyclin partners for activation of kinase activity. The INK4 proteins inhibit CDK activity by directly binding to monomeric CDK4 or CDK6. In contrast, Cip and Kip inhibitors inactivate CDKs by binding to cyclin-CDK complexes. Cyclin-CDK complexes are activated by phosphorylation of the CDK subunit by cyclin-dependent activating kinase (CAK) that contains three subunits: CDK7, cyclin H, and MAT1. By contrast, cyclin-CDK complexes are inhibited by phosphorylation in adjacent threonine and tyrosine residues by the dual-specificity protein kinases, WEE1 and MYT1. These inhibitory phosphorylations can be reversed by the dual-specificity CDC25 phosphatases that dephosphorylate the CDKs at the same amino acid residues. Cyc is cyclin.

(Reproduced from reference Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2005;30(11):630–41, with permission from Elsevier).


8.2.3


In Vivo Functions of Cyclins and CDKs as Revealed by Gene Knockout in Mice


Numerous studies have investigated the in vivo functions of cyclins and CDKs in knockout mice with the genes deleted either singly or in combination. Since it is not the intent of this chapter to review all of the phenotypes of the knockout mice, the readers are referred to the many excellent recent review articles that summarize the findings of these studies. From these studies, it becomes clear that most of the cyclins and CDKs, although previously considered essential for cell proliferation, have turned out to be dispensable. Several compensatory mechanisms were uncovered among cyclins and CDKs. The particularly unexpected finding is that CDK2, thought to be a master regulator of the cell cycle, is dispensable for the regulation of the cell cycle with both CDK4 and CDK1 covering CDK2’s functions. In fact, CDK1 alone is able to drive the mammalian cell cycle, indicating that the regulation of the mammalian cell cycle is highly conserved.


8.2.4


CDK Inhibitors (CKIs)


CDK inhibitors (CKIs) are proteins that constrain the activities of CDKs. Two classes of CDK inhibitors have been described. The first class includes the INK4 proteins ( in hibitors of CD K4 ). Four such INK4 proteins have been identified: p16 INK4a (also known as CDK inhibitor 2A or CDKN2A), p15 INK4b (CDKN2B), p18 INK4c (CDKN2C), and p19 INK4d (CDKN2D). INK4 proteins specifically bind to and inhibit monomeric CDK4 and CDK6 proteins. The second class of CKIs includes the Cip/Kip ( C DK- i nteracting protein/CD K – i nteracting p rotein) family of proteins which are more broadly acting than the INK4 family of proteins and do so by binding to cyclin-CDK complexes. There are three members of the Cip/Kip family of CKIs: p21 Cip1 (also called CDK inhibitor 1A or CDKN1A), p27 Kip1 (CDKN1B), and p57 Kip2 (CDKN1C). Cip and Kip inhibitors block CDK activity by forming inactive trimeric complexes (cyclin E-CDK2, cyclin A-CDK2, cyclin B-CDK1, and possibly cyclin D-CDK4 and cyclin D-CDK6), thus exerting a much broader effect on the progression of the cell cycle. Fig. 8.5 summarizes the multiple regulatory mechanisms by which CDK activities are regulated.




8.3


Checkpoints


The cell cycle contains several checkpoints to monitor and regulate its progression. Checkpoints are positioned at specific locations in the cell cycle to allow verification of phase processes and repair of DNA damage. A cell cannot proceed from one phase to the next without satisfying all of the checkpoint requirements. An important function of many of the cell cycle checkpoints is to assess DNA damage. Upon detection of DNA damage, the checkpoint initiates a signal cascade to either arrest the cell cycle until repairs are properly made, or if repairs are not possible, to target the cell for destruction via apoptosis as a means to maintain genomic integrity. In the cell cycle, there are three specific checkpoints for damaged or incompletely replicated DNA: G 1 /S, G 2 /M, and intra-S checkpoints. These checkpoints are patrolled by some of the CKIs described above. A fourth important and specific checkpoint occurs in mitosis, the so-called mitotic checkpoint or SAC. This checkpoint is designed to monitor proper alignment of the chromosomes during mitosis. Anaphase cannot proceed unless this checkpoint is satisfied. The locations of the various checkpoints in the cell cycle are illustrated in Fig. 8.6 . The various cell cycle checkpoint pathways in response to DNA damage are summarized in Fig. 8.7 .




Fig. 8.6


The cell cycle checkpoints. The locations of the various checkpoints (STOP signs) and the primary defects the checkpoints are designed to monitor are shown.



Fig. 8.7


A simplified scheme of the cell cycle checkpoint pathways in response to DNA damage. The black arrows indicate activating and red lines indicate inhibitory actions.


8.3.1


G 1 /S Checkpoint


The G 1 /S checkpoint (also called the G 1 checkpoint) is located near the end of the G 1 phase; just before the entry into S phase ( Fig. 8.6 ). In mammalian cells, the G 1 checkpoint is the restriction or R point ( Fig. 8.4 ). This is a point where cells typically arrest the cell cycle if environmental conditions are unfavorable for cell division, such as the presence of DNA damage or lack of growth factors. The G 1 checkpoint is controlled by both the INK4 and Cip/Kip families of CKIs. INK4 proteins specifically bind to CDK4 and CDK6 and inhibit their activity. Enforced expression of INK4 proteins arrest cells in the G 1 phase in an RB-dependent manner. Here CDK4 is redistributed from cyclin D-CDK4 complexes to INK4-CDK4 complexes, and unbound D-type cyclin is rapidly degraded by ubiquitination-mediated proteasomal pathway. Also, in early G 1 phase, the cyclin E-CDK2 and cyclin A-CDK2 complexes are inhibited by bound p21 Cip1 and p27 Kip1 . In addition, cyclin D-CDK4/6 complexes bind p21 Cip1 and p27 Kip1 . Loss of D-type cyclins therefore prevents the titration of p21 Cip1 and p27 Kip1 by cyclin D-CDK4/6 complexes away from the cyclin E-CDK2 and cyclin A-CDK2 complexes. As a result, there is complete inhibition of cyclin E-CDK2 and cyclin A-CDK2 activities as well as RB phosphorylation, leading to exit from the G 1 phase. Conversely, growth-induced or oncogenic-induced expression of cyclin D allows its interaction with CDK4/6 by competing with INK4 for binding. The binding of cyclin D-CDK4/6 complexes to p21 Cip1 and p27 Kip1 releases the inhibitors from the cyclin E-CDK2 and cyclin A-CDK2 complexes. This unleashes cyclin E-CDK2 and cyclin A-CDK2 activity, allowing further RB phosphorylation, exit from G 1 and entry into S phase.


The G 1 /S checkpoint is activated upon detection of DNA damage. The mammalian DNA-damage response is a complex network, involving a multitude of proteins that include “sensor” proteins that sense the damage and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell cycle checkpoints, cellular senescence, and apoptosis. In response to DNA damage, signals initiated by the sensors rapidly transduce to the ATM (ataxia telangiectasia, mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases, which phosphorylate a great number of substrates. Among the substrates phosphorylated by activated ATM and ATR are the checkpoint serine/threonine kinases, CHK1 (checkpoint kinase 1) and CHK2 (checkpoint kinase 2). To prevent entry into S phase, CHK1 and CHK2 phosphorylate the cell cycle regulatory phosphatase CDC25A, leading to its ubiquitin-mediated proteolysis. Inactivation of CDC25A leads to sustained inhibitory phosphorylation of cyclin E-CDK2 complexes, thus preventing G 1 /S transition ( Fig. 8.5 ). Both ATM and ATR belong to the phosphatidylinositol-3-kinase-like kinase family (PIKKs), which also includes a third member of the DNA damage response transducer, DNA-PKcs (DNA-dependent protein kinase). DNA-PKcs appears to regulate a smaller number of targets and plays a role primarily in nonhomologous end joining (NHEJ) of double-strand DNA breaks. ATM/ATR and CHK1/CHK2 kinases also target the tumor suppressor, p53. The phosphorylation of p53 by ATM/ATR inhibits its association with MDM2, an E3 ubiquitin ligase normally functions to keep the p53 level low, and this results in stabilization of the p53 protein. Subsequently, p53 transcriptionally activates expression of the p21 Cip1 gene, which in turn inhibits cyclin E-CDK2 and prevents G 1 /S transition. Lastly, rapid degradation of cyclin D1 in response to DNA damage occurs that is independent of p53. The reduced cyclin D1 protein decreases the amount of cyclin D-CDK4/6 complexes, resulting in the redistribution of p21 Cip1 to cyclin E-CDK2 complexes, resulting in the latter’s inactivation.


8.3.2


G 2 /M Checkpoint


The G 2 /M checkpoint (also known as G 2 checkpoint) prevents cells from initiating mitosis when they experience DNA damage while in G 2 , when they progress into G 2 with either unrepaired DNA sustained during the previous S or G 1 phase, or when they possess incompletely replicated DNA from S phase. The critical target of the G 2 checkpoint is the mitosis-promoting activity of the cyclin B-CDK1 complexes, whose activation after genotoxic stresses is inhibited by ATM/ATR, CHK1/CHK2-mediated degradation of CDC25 family of phosphatases, which normally activate CDK1 at the G 2 /M boundary. In addition, other regulators of CDC25 and cyclin B-CDK1, such as the Polo-like kinases (PLKs) are targeted by DNA damage-induced mechanisms. Finally, the maintenance of the G 2 checkpoint is dependent on the transcriptional programs regulated by p53, leading to an induction of cell cycle inhibitors such as p21 Cip1 , growth arrest and DNA damage-inducible 45 (GADD45), and 14-3-3σ proteins. These proteins cooperatively inhibit cyclin B-CDK1 activity by directly binding to cyclin B-CDK1 (p21 Cip1 ), dissociating CDK1 from cyclin B (GADD45), and sequestering CDK1 in the cytoplasm (14-3-3σ), resulting in G 2 arrest.


8.3.3


Intra-S Checkpoint


While proliferating cells respond to genotoxic stresses by activating checkpoint responses that impose durable cell cycle arrest in G 1 or G 2 , before entry into S phase or mitosis, respectively, cells that experience genotoxic stresses during DNA replication can only delay their progression through the S phase in a transient fashion. If the damage is not repaired during the delay, cells exit S phase and arrest upon reaching the G 2 checkpoint. Nonetheless, the intra-S checkpoint is important for the maintenance of genomic stability as DNA replication is a vulnerable period of the cell cycle in which errors occur both endogenously or are introduced exogenously. When the intra-S checkpoint is activated, both replication initiation and fork progression are inhibited, thus reducing the rate of DNA replication. Studies have revealed numerous proteins that are involved in the control of intra-S checkpoint. Among these, activation of ATM and ATR is necessary to initiate intra-S checkpoint upon sensing DNA double-strand breaks (DSBs). Activated ATM and ATR then activates CHK1 and CHK2 kinases, which phosphorylate CDC25A, leading to its ubiquitin-proteosome-dependent degradation. This results in persistent inhibitory phosphorylation of CDK2 in the cyclin A-CDK2 complexes, which, in turn, prevents firing of the replication origins. A second independent pathway is involved in slowing down the replication rate in cells that have suffered from DNA damage. This effect is mediated by ATM-dependent phosphorylation of a cohesion protein, structural maintenance of chromosomes-1 (SMC-1). However, the mechanism by which phosphorylated SMC-1 interferes with DNA replication remains unknown.


8.3.4


Mitotic Checkpoint or SAC


Mitosis is the process in which a cell divides itself into two halves, each with an identical set of chromosomes ( Fig. 8.2 ). The central regulator of this process is the mitotic checkpoint, also known as the spindle assembly checkpoint or SAC, a signaling mechanism that arrests the progression of metaphase to anaphase until all chromosomes are attached to the mitotic spindles. This signal is akin to an “anaphase wait” signal that is generated at the kinetochores of unattached chromosomes and is extinguished once all kinetochores are properly attached to the spindles ( Fig. 8.2 ). Thus, sister chromatids are separated only when they are in a position to be equally distributed to the two daughter cells. Accordingly, the mitotic checkpoint serves to prevent chromosome mis-segregation.


The proteins that control mitotic checkpoint were originally identified by screens for mutations that bypassed the ability of wild type S. cerevisiae to arrest in mitosis in the presence of spindle poisons. The genes identified include MAD (mitotic-arrest deficient), MAD1, MAD2, MAD3 (BUBR1 in humans), and BUB1 (budding uninhibited by benzimidazole 1). It was later found that these genes are conserved in all eukaryotes. When activated, these SAC proteins target CDC20, which is a co-factor of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). Specifically, SAC inhibits the ability of CDC20 to activate APC/C-mediated ubiquitination of two key substrates, cyclin B and securin, thus preventing their degradation by the 26S proteosome. Proteolysis of cyclin B inactivates CDK1, allowing the cells to exit from mitosis. On the other hand, destruction of securin leads to activation of separase, which is required to cleave the cohesion complex that holds sister chromatids together in order to execute anaphase. Therefore, by keeping CDC20 in check, the SAC allows the chromosomes to properly align on the metaphase plate and attached to the two spindle poles through mitotic spindles. Once the chromosomes are properly oriented, the checkpoint is extinguished, relieving the mitotic arrest and allowing anaphase to proceed.




8.4


Noncanonical Functions of Cyclins, CDKs, and CKIs


Close cooperation among cyclins, CDKs, and CKIs is necessary for ensuring orderly progression through the cell cycle. However, evidence has emerged that the roles of this trio are beyond cell cycle regulation. The “noncanonical” functions of cyclins, CDKs and CKIs involve myriads of other cellular processes such as transcription, DNA damage repair, apoptosis, cell differentiation, epigenetic regulation, stem cell self-renewal, metabolism, and the immune response. Some of these functions are performed by cyclins or CDKs independent of their respective cell cycle partners, suggesting that there is substantial divergence in their functions during evolution. For example, D-type cyclins, independent of any associated kinase activity, are known to have direct roles in regulating transcription by interacting with many transcription factors to activate or repress transcription of specific genes. Similarly CDK6, but not CDK4, can regulate angiogenesis and myloid differentiation, respectively, by modulating the transcriptional activity of JUN and RUNX1.


In addition to regulating the cell cycle, the trio of cyclins, CDKs, and CKIs exerts important functions in the repair of DNA damage sustained from DSBs. DNA DSBs are repaired by two different mechanisms: homologous recombination and NHEJ. Cyclin D1 has been shown to localize to DNA DSBs and to recruit RAD51, which activates HR-mediated DNA repair. CDK2 was also shown to support HR by promoting the interaction between breast cancer type 1 susceptibility protein (BRCA1) and the MRE11 exonuclease, leading to the resection of DSBs. These observations suggest that there is a profound, two-way connection between DNA damage repair and cell cycle control.


The Cip/Kip family of CKIs (p21 Cip1 , p27 Kip1 , and p57 Kip2 ) also exhibit functions independent of their ability to inhibit cyclin-CDK complexes. They have been found to be key regulators of transcription, apoptosis, and actin cytoskeletal dynamics. For example, p21 Cip1 binds to the transcription factors E2F-1, STAT3 and c-Myc to inhibit their transcriptional activities, and binds to p300/CBP to block its transcriptional repressor activity. p21 Cip1 also binds and inhibits JNK1/SAPK kinase and MAPK-kinase-kinase ASK1/MEKK5 to block stress-induced apoptosis. The antiapoptotic activities are attributed to the cytoplasmic pool of p21 Cip1 . Finally all three Cip/Kip CKIs regulate actin cytoskeletal dynamics by modulating the RhoA-ROCK-LIMK-cofilin pathway, leading to redistribution of monomeric actin and contributing to increase cell motility and morphological changes. These divergent functions are performed in distinct cellular compartments and contribute to the seemingly contradictory observation that the CKIs can both suppress or promote tumor formation.




8.5


Pathological Consequences of Cell Cycle Deregulation or Dysregulation


Because regulation of the cell cycle is central to the control of cell proliferation, it is not surprising that cancers are often the results of deregulation or dysregulation of the cell cycle. Take colorectal cancer, for example, recent genomic-scale sequencing studies have identified numerous somatic mutations in genes that possibly are involved in the formation of cancer. Among these, some of the most highly ranked “cancer genes” are either directly or indirectly involved in the regulation of the cell cycle. Examples include p53, adenomatous polyposis coli (APC), KRAS, F-box and WD40 domain protein 7 (FBXW7), and phosphatidylinositol 3-kinase, catalytic, alpha subunit (PI3KCA). Here we briefly review some of the common cancer genes with cell cycle regulatory functions.


8.5.1


Retinoblastoma (RB) Tumor Suppressor Gene


The RB tumor suppressor protein limits cell proliferation by preventing entry into the S phase of the cell cycle. RB achieves its inhibitory effect by blocking the activity of E2F. Progression into S phase occurs when the ability of RB to suppress E2F is disrupted by the hyperphosphorylation of RB by cyclin D- and cyclin E-dependent CDKs in the G 1 phase of the cell cycle. The INK4 family of CKIs, particularly p16 INKa , directly inhibits activities of the cyclin D-dependent kinases, CDK4 and CDK6, thus maintaining RB in its active, antiproliferative state. Functional disruption of the tumor suppressors, p16 INKa and RB, or overexpression of the proto-oncogene products, cyclin D1 and CDK4, occur in many human cancers, prompting the speculation that disabling the “RB pathway” is an essential part of cancer formation. In addition to being causative in RB, loss of RB has been found in many other cancers. Similarly, inactivating mutations of 16 INK4a have been identified in numerous tumors. The often exclusive nature of mutations that result in RB or p16 INK4a loss, and/or cyclin D1 or CDK4 overexpression, suggest that each of these cell cycle regulatory genes exerts a critical function in the RB pathway of cancer formation. As such RB and its effectors prove to be potentially powerful predictive, prognostic and therapeutic target in cancer.


8.5.2


p53 and INK4a/ARF Tumor Suppressor Genes


The tumor suppressor p53 is mutated in more than 50% of human cancers. It has been estimated that cancers derived from over 50 human cell types or tissues contain mutations in the p53 gene. p53 is a labile protein but accumulates in response to cellular stresses from DNA damage, hypoxia, or oncogenic activation. Upon stabilization and activation, p53 initiates a transcriptional program that triggers either cell cycle arrest or apoptosis. Among the p53-responsive genes are p21 Cip1 , BCL2-associated X protein (BAX), and mouse double-minute 2, homolog (MDM2). While p21 Cip1 regulates progression of the cell cycle by inhibiting cyclins (E, A, and B)-CDK2 complexes, BAX causes apoptosis. The transcriptional induction of MDM2 by p53 is a negative feedback mechanism as binding of MDM2, an E3 ubiquitin ligase, to p53 induces ubiquitination of p53 and subsequent degradation. MDM2, in turn, is negatively regulated by the ARF (alternative reading frame) tumor suppressor (p14 ARF in humans and p19 ARF in mice). ARF directly associates with MDM2 to block its interaction with p53, therefore stabilizing p53. Thus, disruption of the ARF-MDM2-p53 signaling pathway is a common feature in cancers. This is supported by the finding that MDM2 is overexpressed in 5%–10% of human cancers, whereas ARF is silenced or deleted in many others. It is of interest to note that ARF is derived from an alternative reading frame in exon 2 of the INK4a gene. Loss of the INK4a/ARF locus therefore predisposes to many tumor types due to the dual disruption of the RB-E2F and MDM2-p53 pathways.


8.5.3


hCDC4/FBXW7 Tumor Suppressor Gene


Abundant evidence indicates that ubiquitin-dependent proteolysis regulates many aspects of the cell cycle and that dysregulation of the ubiquitin-proteosome pathway contributes to the formation of cancers. The proteolytic regulation of cell division is primarily controlled by two ubiquitin ligase systems, APC/C and SCF. The APC/C ubiquitin ligase is a multimeric protein complex that regulates chromosomes segregation (see above, The Mitotic Checkpoint or Spindle Assembly Checkpoint). SCF ligase complexes are structurally similar to APC/C and composed of an invariable core complex of SKP1, CUL1, and RBX1, and associated with a variable member of the F-box protein family that serves as the substrate recognition component. Among the approximately 70 different F-box proteins that were identified, the human homologue of yeast CDC4 (hCDC), also known as F-box and WD40-domain protein 7 (FBXW7), has been extensively characterized and implicated in human tumorigenesis. For example, among the approximately 140 mutated “cancer genes” identified in a recent genomic screen in colorectal cancers, FBXW7 ranks fifth as the most frequently mutated gene (after APC, KRAS, p53, and PI3K). Recurrent alterations in FBXW7 are also found in colorectal adenomas.


Human FBXW7 exists in three different isoforms, α, β, and γ, each with a unique amino terminal end fused to a common carboxyl terminal. The interaction between FBXW7 and its substrates depends on phosphorylation of the substrate within a motif called the CDC4-phophodegredron or CPD. This feature enables FBXW7 to simultaneously regulate a host of substrates by ubiquitination. Among the many substrates for FBXW7, some are critically involved in the regulation of the cell cycle such as cyclin E, c-Myc, c-Jun, and Notch. Mutations in the FBXW7 gene therefore lead to stabilization and elevated levels of these substrates. It is no wonder that FBXW7 is such a commonly mutated gene in human cancers.


One of the best characterized substrates of FBXW7 is cyclin E, which is essential for entry into S phase from G 1 phase in the cell cycle. Cyclin E level is elevated or dysregulated in many human cancers, resulting in dysfunction of the cell cycle. The consequences of cyclin E deregulation are multitude and include genetic instability, centrosome amplification, and fork collapse during DNA replication. Several studies subsequently identified cyclin E as a substrate for FBXW7, which mediates the phosphorylation- and ubiquitination-dependent degradation of cyclin E. Thus, it appears that tumorigenesis secondary to cyclin E deregulation is linked to altered function of FBXW7/hCDC4.


8.5.4


Chromosomal Instability (CIN) and Aneuploidy as Consequences of an Aberrant Mitotic Checkpoint


Genetic instability has long been recognized as an integral part of human cancers. In colorectal cancer (CRC), there are two major forms of genetic instability: microsatellite instability (MIN) and chromosomal instability (CIN). MIN tumors have mutations in the DNA mismatch repair (MMR) genes and accounts for approximately 15%–20% of sporadic CRC. The remainders of the sporadic CRC have CIN, which are frequently aneuploid, that is, they exhibit alterations in the number of chromosomes. It has been suggested that CIN is the driving force for the formation of aneuploidy and tumorigenesis. Although there has not been a unified mechanism responsible for CIN, defects in several cellular processes have been causally linked to its formation. These include chromosome dynamics (e.g., chromosome condensation, segregation, cohesion, and kinetochore-spindle interaction), centrosome duplication, cell cycle checkpoints (include G 1 , S, G 2, and the SACs), DNA damage repair pathway, and telomere functions. Among these potential factors contributing to CIN, the mitotic checkpoint is probably the most important one since it is an essential part of the cell cycle that ensures equal distribution of chromosomes upon the conclusion of cell division. Studies in mice lacking specific components of the mitotic checkpoint support this view. Mice with genetically reduced levels of mitotic checkpoint proteins including MAD1, MAD2, BUB1, BUB3, BUBR1, and centromeres protein E (CENP-E) all have increased level of aneuploidy and CIN, with the eventual formation of tumors in some animals. Importantly, somatic mutations of many of the same genes have been identified in human cancers, indicating the importance of the mitotic checkpoint in maintaining genomic integrity. These findings render the concept of exploiting the genetic instability of cancer cells through therapeutic intervention of the mitotic checkpoint a distinct possibility.


8.5.5


The Adenomatous Polyposis Coli Tumor Suppressor Gene


Germline mutations of the APC (note: different from APC/C) tumor suppressor gene cause familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by the presence of numerous colonic adenomas and colon cancer early in life. Somatic mutations in the APC gene were subsequently found to be present in the majority of sporadic colorectal cancer. Its involvement in tumor initiation leads to the hypothesis that APC functions as a “gatekeeper” of colonic epithelial cell proliferation and is responsible for the maintenance of colonic epithelial cell renewal. A telling insight into the function of APC came from the observation that it interacts with β-catenin. β-Catenin is implicated in regulating the Wnt signaling pathway of growth control. Particularly, Wnt signaling is now a well-established central mechanism for regulating proliferation of intestinal epithelial stem cells that are the precursors to all subsequent intestinal epithelial cell lineages.


Wnt signaling is normally absent in a quiescent, noncycling cell. This is accompanied by the sequestration of β-catenin in a “destruction complex” in the cytoplasm that includes APC, Axin, casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3) ( Fig. 8.8 A). This complex leads to the phosphorylation of β-catenin, which is then degraded by ubiquitin-mediated proteasomal degradation. When Wnt, a secreted glycoprotein, is present, it binds to the cell surface receptors Frizzled (Fz) and lipoprotein receptor-related protein (LRP). This leads to activation of the protein disheveled (Dsh) and subsequent release of β-catenin from the destruction complex, resulting in accumulation of free β-catenin in the cytoplasm ( Fig. 8.8 B). Some of this free β-catenin is shuttled into the nucleus where it becomes associated with the transcription factor, T-cell factor (TCF) to activate target gene expression ( Fig. 8.8 B). Among the genes stimulated by the β-catenin/TCF complexes are those encoding cyclin D1 and c-Myc, both of which are critical for the progression of the cell cycle. It is important to note that mutational inactivation of APC or constitutional mutational activation of β-catenin, two common events in the pathogenesis of colorectal cancer, results in a similar net effect of nuclear β-catenin accumulation to that seen during Wnt signaling. These mutations then lead to unregulated cell proliferation.




Fig. 8.8


Schematic presentation of the Wnt signaling pathway. (A) Wnt is absent and (B) Wnt is present. β-cat = β-catenin; Fz = Frizzled; LRP = lipoprotein receptor-related protein; Dsh = disheveled; CK1 = casein kinase 1; GSK3 = glycogen synthase kinase 3; TCF = T-cell factor.

(Adapted with from reference Yang VW. APC as a checkpoint gene: the beginning or the end? Gastroenterology 2002;123(3):935–9, with permission from Elsevier.)


APC has also been implicated in the regulation of mitosis in a β-catenin-independent manner. Here APC is localized to the ends of microtubules embedded in kinetochores and forms a complex with several SAC proteins. This finding suggests that APC is involved in chromosome segregation. The role of APC in regulation of mitosis is consistent with the finding that mutations in the APC gene cause chromosomal instability. Thus, APC may fulfill two requirements for a colonic epithelial cell to develop into colon cancer—the cell must acquire a selective advantage to allow for an initial clonal expansion, and generate genetic instability to allow for multiple hits in other genes that are responsible for tumor progression and malignant transformation.


8.5.6


Cell Cycle Regulators as Targets for Cancer Treatment


Because deregulation or dysregulation of the cell cycle is frequently found in cancer, the cell cycle regulatory proteins are logical targets for development of novel theories for cancer. Recent studies have demonstrated that orally available small-molecule inhibitors of the cyclin D-dependent CDK4 and CDK6, when combined with established therapies, have potential in the treatment of certain cancers. A recently completed phase 3 clinical trial is an example of a success story that the combination of palbociclib, a CDK4-CDK6 inhibitor, and letrozole, an aromatase inhibitor, is highly effective in the treatment of advanced breast cancer. Given that many additional novel similar agents are in various stages of development, cell cycle-based targeted therapy promises to become part of a new armamentarium in the combat against cancer.




8.6


Conclusion


The cell cycle is a fundamental cellular process in which a cell duplicates itself in a highly faithful manner to maintain genomic integrity. The cell cycle is divided into several distinct phases that are controlled by specific pairs of cyclin-CDK. The cell cycle also contains specific checkpoints with which to monitor the presence of damaged or incompletely replicated DNA in interphase, or unaligned chromosomes in mitosis. Dysregulation or deregulation of the cell cycle often have pathological consequences and a good example is cancer. Hence, many of the cell cycle regulators act as tumor suppressors or oncoproteins such as Rb, p53, FBXW7, and cyclins. The relevance of cell cycle regulation also has an impact on the physiology of the gastrointestinal tract as the epithelium is composed of rapidly proliferating cells. A prominent example is the crucial role of the Wnt signaling pathway in regulating proliferation of intestinal stem cells and that a critical component of the Wnt pathway, the APC protein, is mutated in the majority of colorectal cancer. Recent clinical studies have also shown promising results in cancer treatment by targeting cell cycle regulatory proteins. Thus, a clear understanding of the cell cycle machinery is essential not only for understanding the mechanisms regulating proliferation of intestinal epithelial cells, but developing novel therapies for cancer.


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