TheÂ cell cycle is the series of events that takes place in aÂ cellÂ leading to its division and replication. In prokaryotic cells, the cell cycle occurs via a process termedÂ binary fission. In eukaryotic cells, the cell cycle can be divided in different phases. The two primary phases being interphase during which the cell grows, accumulates nutrients needed for mitosis andÂ duplicates its DNA, and theÂ mitosisÂ (M) phase, during which the cell splits itself into two distinct cells, called "daughter cells". The cell-division cycle is a vital process by which a single-celledÂ fertilized eggÂ develops into a mature organism, as well as the process by whichÂ hair,Â skin,Â blood cells, and some internal organs are renewed.
Apoptosis is the process ofÂ programmed cell death that may occur in multicellular organisms (Green & Douglas, 2011). Biochemical events lead to morphological cell changes and death. These changes include blebbing, loss of cell membrane integrity, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. UnlikeÂ necrosis, apoptosis produces cell fragments called apoptotic bodies that surrounding cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage (Alberts et al, 2008).
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Apoptosis, in general, confers advantages during an organism's life cycle. For example, the differentiation of fingers and toes in a developing human embryoÂ occurs due to apoptosis occurring in the cells between the digits separating them. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases whereas excessive apoptosis causesÂ atrophy. Insufficient amounts result in uncontrolled cell proliferation, such asÂ cancer.
NecrosisÂ is the prematureÂ deathÂ ofÂ cellsÂ and living tissue due to factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast toÂ apoptosis, which is a naturally occurring cause of cellular death. Necrosis is almost always detrimental and can be fatal. Cells that die due to necrosis do not usually send the sameÂ chemical signalsÂ to the immune system that cells undergoing apoptosis do. This prevents nearbyÂ phagocytesÂ from locating andÂ engulfingÂ the dead cells, leading to a build-up of dead tissue and cell debris at or near the site of the cell death. For this reason, it is often necessary to remove necrotic tissueÂ surgically, a process known asÂ debridement.
Knowledge about the cell cycle and its possible death mechanisms is essential for any cell biologist so as to identify characteristics of these processes to differentiate between them. It is also a very important aspect that has to be taken into account when diseases are being studied to understand the different mechanisms of pathology on a cellular level.
The Cell Cyclehttp://1.bp.blogspot.com/_J35J2fUbSoY/TVCfa8gmxbI/AAAAAAAAAB8/Z5BCb1RRC6A/s1600/cellcycle.jpg
Fig. 1: The Cell Cycle
Table 1: Phases of the cell cycle and their descriptions.
A resting phase where the cell has left the cycle and has stopped dividing.
Cells increase in size in Gap 1. TheÂ G1Â checkpointÂ control mechanism ensures that everything is ready forÂ DNAÂ synthesis.
DNA replicationÂ occurs during this phase.
During the gap between DNA synthesis and mitosis, the cell will continue to grow. TheG2Â checkpointÂ control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.
Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.
Resting (G0) Phase
Nonproliferative cells in multicellularÂ eukaryotesÂ generally enter the quiescent G0Â state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case forÂ neurons). This is very common for cells that are fullyÂ differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell byÂ apoptosis.
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Interphase proceeds in three stages, G1, S, and G2.
The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis is calledÂ G1Â (G indicatingÂ gap). It is also called the growth phase. During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1Â is highly variable, even among different cells of the same species (Smith & Martin, 1973).
The ensuingÂ S phaseÂ starts whenÂ DNAÂ synthesis commences; when it is complete, all of theÂ chromosomesÂ have been replicated, i.e., each chromosome has sisterÂ chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled. Rates of RNAÂ transcriptionÂ and protein synthesis are very low during this phase. An exception to this isÂ histoneÂ production, most of which occurs during the S phase (Nelson et al, 2002).
The cell enters theÂ G2Â phase, which lasts until the cell enters mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production ofÂ microtubules, which are required during the process of mitosis. Inhibition of protein synthesis during G2Â phase prevents the cell from undergoing mitosis.
Mitosis (M Phase/Mitotic phase)
The relatively briefÂ M phaseÂ consists of nuclear division or karyokinesis. The M phase has been broken down into several distinct phases, sequentially known as prophase, metaphase, anaphase, telophase which is then followed by cytokinesisÂ (cytokinesis is not part of mitosis but is an event that directly follows mitosis in which cytoplasm is divided into two daughter cells)
MitosisÂ is the process by which aÂ eukaryoticÂ cell separates theÂ chromosomesÂ in itsÂ cell nucleusÂ into two identical sets in two nuclei (Rubenstein, Irwin, & Wick, 2008). Â It is generally followed immediately by cytokinesis, which divides the nuclei,Â cytoplasm,Â organellesÂ andÂ cell membraneÂ into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define theÂ mitotic (M) phaseÂ of the cell cycle - theÂ divisionÂ of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.
Regulation of the Cell Cycle
Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.
Cyclins and CDKs
Two key classes of regulatory molecules,Â cyclinsÂ andÂ cyclin-dependent kinasesÂ (CDK's), determine a cell's progress through the cell cycle (Nigg, 1995). Cyclins form the regulatory subunits and CDK's the catalytic subunits of an activatedÂ heterodimer; cyclins have no catalytic activity and CDK's are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDK's perform phosphorylationÂ that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDK's are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals (Robbins et al, 2004).
Mechanism of cyclin-CDK interaction
Upon receiving a pro-mitotic extracellular signal, G1Â cyclin-CDKÂ complexes become active to prepare the cell for S phase, promoting the expression ofÂ transcription factorsÂ that in turn promote the expression of S cyclins and of enzymes required forÂ DNA replication. The G1Â cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them forÂ ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by theÂ proteasome.
Active S cyclin-CDK complexes phosphorylate proteins that make up theÂ pre-replication complexesÂ assembled during G1Â phase on DNAÂ replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell'sÂ genomeÂ will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, extra copies of certain genes is also deleterious to the daughter cells.
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Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2Â phases, promote the initiation ofÂ mitosisÂ by stimulating downstream proteins involved in chromosome condensation andÂ mitotic spindleÂ assembly. A critical complex activated during this process is aÂ ubiquitin ligaseÂ known as theÂ anaphase-promoting complexÂ (APC), which promotes degradation of structural proteins associated with the chromosomalÂ kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.
Interphase generally lasts at least 12 to 24 hours in mammalian tissue. During this period, the cell is constantly synthesizing RNA, producing protein and growing in size.
Action of cyclin-CDK complexes
Cyclin DÂ is the first cyclin produced in the cell cycle, in response to extracellular signals (e.g. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (Rb). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes likeÂ cyclin E,Â cyclin A,DNA polymerase,Â thymidine kinase, etc. Cyclin E thus produced binds toÂ CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1Â to S phase (G1/S transition). Cyclin B along with cdc2 forms the cyclin B-cdc2 complex, which initiates the G2/M transition (Norbury, (1995). Cyclin B-cdc2 complex activation causes breakdown ofÂ nuclear envelopeÂ and initiation ofÂ prophase, and subsequently, its deactivation causes the cell to exit mitosis (Robbins et al, 2004).
Cellular Suicide: Apoptosis
Apoptosis stands out as a form of intentional suicide based on a genetic mechanism. It is a form of cell death characterized by morphological and biochemical measures. Morphological characteristics of apoptosis include cell shrinkage and the cell becomes denser (Kerr, 1971). The chromatin becomes pyknotic (thickened or condense) and packed into smooth masses applied against the nuclear membrane. The nucleus may also break up (karyorhexis). Karyorhexis, or nuclear fragmentation is a feature of apoptosis. However, it is certainly not restricted to apoptosis as it has been seen in a variety of dying (and infected) tissues (Klebs, 1889) ex. neurons can show karyorhexis as a result of ischemia (Squier & Keeling, 1991) and hyperoxia (Ahdab-Barmada, et al. 1986).
In their agony, cells dying by apoptosis emit a number of pseudopodia, a process described as budding (Kerr & Harmon, 1991). The pathogenesis of the budding phenomenon is not understood; perhaps it is related to the final breakup of the cell. The buds may contain any type of organelles, including nuclear fragments, and do not swell; they should not be confused with blebs. Blebs are typical of ischemic cell death. They are blister-like, fluid-filled structures that may pinch off and float away.
Fig. 2: Apoptotic characteristics
These " budding" processes tend to break off and become apoptotic bodies, which may be phagocytized by macrophages or neighboring cells or remain free; however, the cell may also shrink into a dense, rounded mass, as a single apoptotic body. Little or no swelling of mitochondria or other organelles occurs. DNA is broken down into segments due to specific cleavage between nucleosomes. The process is under genetic control (Wyllie, 1994) and can be initiated by an internal clock, or by extracellular agents such as hormones, cytokines, killer cells, and a variety of chemical, physical, and viral agents. Apoptosis can run its course very fast, even in minutes and for this reason apoptosis is remarkably inconspicuous in tissue sections (Weedon, Searle, & Kerr, 1979). In routine sections the best cytological marker of apoptosis is a fragmented nucleus, especially in an isolated cell.
Regulated apoptosis, is essential for embryonic development,immune-system function and the maintenance of tissue homeostasis in multicellular organisms (Ellis, Yuan, & Horvitz, 1991). Dysregulation of apoptosis has been implicated in numerous pathological conditions, including neurodegenerative diseases, autoimmunity and cancer. Apoptosis in mammalian cells is mediated by a family of cysteine proteases known as the caspases (Alnemri, et al. 1996). To keep the apoptotic programme under control, caspases are initially expressed in cells as inactive procaspase precursors. When initiator caspases - such as caspase-8 and caspase-9 - are activated by oligomerization, they cleave the precursor forms of effector caspases, such as caspase-3, caspase-6 and caspase-7 (Thornberry & Lazebnik, 1998). Activated effector caspases in turn cleave a specific set of cellular substrates, resulting in the well-known constellation of biochemical and morphological changes that are associated with the apoptotic phenotype (Thornberry & Lazebnik, 1998). There are two pathways by which caspase activation is triggered - the extrinsic and intrinsic apoptotic pathways. The extrinsic pathway is activated by the engagement of death receptors on the cell surface. Binding of ligands such as FASL and tumour necrosis factor (TNF) to FAS and the TNF receptor (TNFR), respectively, induces the formation of the deathinduced signalling complex (DISC). DISC in turn recruits caspase-8 and promotes the cascade of procaspase activation that follows (Budihardjo, et al. 1999). The intrinsic pathway is triggered by various extracellular and intracellular stresses, such as growth-factor withdrawal, hypoxia, DNA damage and oncogene induction. Signals that are transduced in response to these stresses converge mainly on the mitochondria. A series of biochemical events is induced that results in the permeabilization of the outer mitochondrial membrane (Kluck, et al. 1999), the release of cytochrome c and other proapoptotic molecules, the formation of the apoptosome - a large protein complex that contains cytochrome c, apoptotic protease activating factor 1 (APAF1) and caspase-9 - and caspase activation (Budihardjo, et al. 1999). Among these processes, only the permeabilization step is regulated, in that anti-apoptotic members of the BCL2 family can stop the march towards apoptotic death (Cory & Adams, 2002). Once cytochrome c is released, however, the downstream cascade of caspase activation is irreversible (Goldstein, et al. 2000). Cell death is also modified by other mitochondrial proteins. Endonuclease G21 and apoptosis-inducing factor (AIP) (Lipton, & Bossy-Wetzel, 2002) might induce cell death independently of caspase activation. DIABLO (also known as SMAC) (Verhagen, et al. 2000) and OMI (also known as HTRAZ) (Suzuki, et al. 2001) promote caspase activation by counteracting inhibitor of apoptosis (IAP)-mediated caspase inhibition.
Fig. 2: p53 Apoptotic Pathway (Burns & El-Deiry 1999).
The transcription factor, p53, induces apoptosis in a caspase dependent manner through transactivation of its target genes (see figure 2). p53 induces Fas/APO1, KILLER/DR5, Bax, and PIGs and inhibits Bcl-2 allowing p53 to mediate apoptosis through several caspase dependent mechanisms. The death receptors Fas/APO1 and KILLER/DR5 bind to their ligands and form trimers that recruit adaptor molecules and initiator caspases to their respective cytoplasmic death domains. Activation of these initiator caspases results in the cleavage of the downstream effector caspases and cell death. Induction of Bax and inhibition of Bcl-2 leads to mitochondrial release of cytochrome c and ATP. APAF1 becomes activated upon binding cytochrome c and ATP and cleaves caspase 9. Activated caspase 9 cleaves the downstream effector caspases and apoptosis results. The PIG genes appear to induce apoptosis through the production of reactive oxygen species (ROS) (Burns & El-Deiry 1999).
Necrosis is signaled by irreversible changes in the nucleus (karyolysis, pyknosis, and karyorhexis) and in the cytoplasm (condensation, loss of structure, and fragmentation).
Apoptotic cells are not always recognized by phagocytes and then they may undergo apoptotic necrosis. Necrosis and apoptosis are often considered as two opposite forms of cell death. However, necrosis is not a form of cell death but the end stage of any cell death process. Necrosis is marked by cellular swelling, often accompanied by chromatin condensation and eventually leading to cellular and nuclear lysis with subsequent inflammation. Apparently, apoptotic cells that are not phagocyted show several of these necrotic features, except for an inflammation process (Majno & Joris, 1995).
Fig. 4: Necrosis vs. Apoptosis