Cell cycle

Cell cycle

Overview

The cell cycle, or cell-division cycle, is the series of events that takes place in a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 leading to its division and duplication (replication). In cells without a nucleus (prokaryotic), the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle can be divided in three periods: interphase
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

—and the mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

 (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells" and the final phase, Cytokinesis, where the new cell is completely divided.
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The cell cycle, or cell-division cycle, is the series of events that takes place in a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 leading to its division and duplication (replication). In cells without a nucleus (prokaryotic), the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle can be divided in three periods: interphase
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

—and the mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

 (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells" and the final phase, Cytokinesis, where the new cell is completely divided. The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair
Hair
Hair is a filamentous biomaterial, that grows from follicles found in the dermis. Found exclusively in mammals, hair is one of the defining characteristics of the mammalian class....

, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

, blood cell
Blood cell
A blood cell, also called a hematocyte, is a cell normally found in blood. In mammals, these fall into three general categories:* red blood cells — Erythrocytes* white blood cells — Leukocytes* platelets — Thrombocytes...

s, and some internal organs are renewed.

Phases


The cell cycle consists of four distinct phases: G1 phase
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...

, S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...

 (synthesis), G2 phase
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...

 (collectively known as interphase
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

) and M phase
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

 (mitosis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...

, in which the cell's cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 divides in half forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence
Quiescence
Quiescence may refer to:*Quiescence search, in Game searching in artificial intelligence, a quiescent state is one in which a game is considered stable and unlikely to change drastically the next few plays...

 called G0 phase
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...

.
State Phase Abbreviation Description
quiescent/
senescent
Gap 0
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...

G0 A resting phase where the cell has left the cycle and has stopped dividing.
Interphase
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

Gap 1
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...

G1 Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 synthesis.
Synthesis
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...

S DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

 occurs during this phase.
Gap 2
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...

G2 During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.
Cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...

Mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

M 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.


After cell division, each of the daughter cells begin the interphase
Interphase
Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

 of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

Resting (G0 phase)


The term "post-mitotic" is sometimes used to refer to both quiescent
G0 phase
The G0 phase is a period in the cell cycle in which cells exist in a quiescent state. G0 phase is viewed as either an extended G1 phase, where the cell is neither dividing nor preparing to divide, or a distinct quiescent stage that occurs outside of the cell cycle...

 and senescent cells. Nonproliferative cells in multicellular eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

s generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s). This is very common for cells that are fully differentiated
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

. 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 by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. As well, growth and division of such a cell could become cancerous.

Interphase


Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during the interphase. Interphase proceeds in three stages, G1, S, and G2. Cell division operates in a cycle. Therefore, interphase is preceded by the previous cycle of mitosis and cytokinesis. Interphase is also known as preparatory phase, in this stage nucleus and cytochrome division does not occur.

G1 phase


The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis is called G1
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...

 (G indicating 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 G1 is highly variable, even among different cells of the same species.

S phase


The ensuing S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...

 starts when DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 synthesis commences; when it is complete, all of the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

s have been replicated, i.e., each chromosome has two (sister) chromatid
Chromatid
A chromatid is one of the two identical copies of DNA making up a duplicated chromosome, which are joined at their centromeres, for the process of cell division . They are called sister chromatids so long as they are joined by the centromeres...

s. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy
Ploidy
Ploidy is the number of sets of chromosomes in a biological cell.Human sex cells have one complete set of chromosomes from the male or female parent. Sex cells, also called gametes, combine to produce somatic cells. Somatic cells, therefore, have twice as many chromosomes. The haploid number is...

 of the cell remains the same. Rates of RNA transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 and protein synthesis are very low during this phase . An exception to this is histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...

 production, most of which appears during the S phase.

G2 phase


The cell then enters the G2 phase
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...

,
which lasts until the cell enters mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production of microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...

s, which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.

Mitosis (M Phase/Mitotic phase)



The relatively brief M phase consists of nuclear division (karyokinesis). The M phase has been broken down into several distinct phases, sequentially known as:
  • prophase
    Prophase
    Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...

    ,
  • metaphase
    Metaphase
    Metaphase, from the ancient Greek μετά and φάσις , is a stage of mitosis in the eukaryotic cell cycle in which condensed & highly coiled chromosomes, carrying genetic information, align in the middle of the cell before being separated into each of the two daughter cells...

    ,
  • anaphase
    Anaphase
    Anaphase, from the ancient Greek ἀνά and φάσις , is the stage of mitosis or meiosis when chromosomes move to opposite poles of the cell....

    ,
  • telophase
    Telophase
    Telophase from the ancient Greek "τελος" and "φασις" , is a stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase events are reversed. Two daughter nuclei form in the cell. The nuclear envelopes of the daughter cells are formed from the...

  • cytokinesis
    Cytokinesis
    Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...

     (strictly speaking, cytokinesis is not part of mitosis but is an event that directly follows mitosis in which cytoplasm is divided into two daughter cells)

Mitosis is the process by which a eukaryotic cell separates the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

s in its cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

 into two identical sets in two nuclei. It is generally followed immediately by cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...

, which divides the nuclei, cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

, organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....

s and cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

 into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle - the division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...

 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.

Mitosis occurs exclusively in eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

 cells, but occurs in different ways in different species. For example, animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...

s undergo an "open" mitosis, where the nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...

 breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans
Aspergillus nidulans
Aspergillus nidulans is one of many species of filamentous fungi in the phylum Ascomycota...

 and Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

 (yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

. Prokaryotic
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...

 cells, which lack a nucleus, divide by a process called binary fission.

The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids
Sister chromatids
Sister chromatids are two identical copies of a chromatid connected by a centromere. Compare sister chromatids to homologous chromosomes, which are the two different copies of the same chromosome that diploid organisms inherit, one from each parent...

 to opposite sides of the cell. The cell then divides in cytokinesis
Cytokinesis
Cytokinesis is the process in which the cytoplasm of a single eukaryotic cell is divided to form two daughter cells. It usually initiates during the late stages of mitosis, and sometimes meiosis, splitting a binucleate cell in two, to ensure that chromosome number is maintained from one generation...

, to produce two identical daughter cells.

Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei. This occurs most notably among the fungi
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...

 and slime mould
Slime mould
Slime mold or mould is a broad term describing protists that use spores to reproduce. Slime molds were formerly classified as fungi, but are no longer considered part of this kingdom....

s, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

 embryonic development. Errors in mitosis can either kill a cell through apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 or cause mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s that may lead to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

.

Regulation of eukaryotic 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.

Role of cyclins and CDKs


Two key classes of regulatory molecules, cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...

s and cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...

s (CDKs), determine a cell's progress through the cell cycle. Leland H. Hartwell
Leland H. Hartwell
Leland Harrison Hartwell is former president and director of the Fred Hutchinson Cancer Research Center in Seattle, Washington. He shared the 2001 Nobel Prize in Physiology or Medicine with Paul Nurse and R...

, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

 for their discovery of these central molecules. Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

; genetic nomenclature in yeast dubs many these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc25
Cdc25
Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...

 or cdc20
CDC20
The cell-division cycle protein 20 is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex , a large 11-13 subunit complex that initiates chromatid separation...

.

Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 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. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.

General mechanism of cyclin-CDK interaction



Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

s that in turn promote the expression of S cyclins and of enzymes required for DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria.  In eukaryotes, they are located in the nucleus and the cytoplasm.  The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...

.

Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complex
Pre-replication complex
A pre-replication complex is a protein complex that forms at the origin of replication during the initiation step of DNA replication. Formation of the pre-RC is required for DNA replication to occur. Complete and faithful replication of the genome ensures that each daughter cell will carry the...

es assembled during G1 phase on DNA replication origins
Origin of replication
The origin of replication is a particular sequence in a genome at which replication is initiated. This can either be DNA replication in living organisms such as prokaryotes and eukaryotes, or RNA replication in RNA viruses, such as double-stranded RNA viruses...

. 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's genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 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, for reasons related to gene copy number
Gene copy number
Copy-number variations —a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted or duplicated on certain...

 effects, possession of extra copies of certain genes is also deleterious to the daughter cells.

Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

 by stimulating downstream proteins involved in chromosome condensation and mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...

 assembly. A critical complex activated during this process is a ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...

 known as the anaphase-promoting complex
Anaphase-promoting complex
Anaphase-Promoting Complex, also called cyclosome , is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin and RING subunit much like SCF...

 (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore
Kinetochore
The kinetochore is the protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart....

. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.

Specific action of cyclin-CDK complexes


Cyclin D
Cyclin D
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition...

 is the first cyclin produced in the cell cycle, in response to extracellular signals (e.g. growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

s). Cyclin D binds to existing CDK4
Cyclin-dependent kinase 4
Cyclin-dependent kinase 4 is part of the cyclin-dependent kinase family.It is regulated by Cyclin D.-Interactions:Cyclin-dependent kinase 4 has been shown to interact with SERTAD1, CDC37, CEBPA, PCNA, Cyclin D3, Cyclin D1, CDKN2C, MyoD, P16, CDKN2B, Drebrin-like and CDKN1B.-External links:...

, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...

 susceptibility protein (Rb
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...

). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F
E2F
E2F is a group of genes that codifies a family of transcription factors in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells...

 responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....

, cyclin A
Cyclin A
Cyclin A is a member of the cyclin family.Cyclin A binds to S phase Cdk2 and is required for the cell to progress through the S phase. Cyclin A/ Cdk2 is inhibited by the complex p21CIP.-External links:*...

, DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....

, thymidine kinase
Thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, . It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2...

, etc. Cyclin E thus produced binds to CDK2
Cyclin-dependent kinase 2
Cyclin-dependent kinase 2 also known as cell division protein kinase 2 is an enzyme that in humans is encoded by the CDK2 gene.-Function:...

, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S transition). Cyclin B along with cdc2 (cdc2 - fission yeasts (CDK1 - mammalia)) forms the cyclin B-cdc2 complex, which initiates the G2/M transition. Cyclin B
Cyclin B
Cyclin B is a member of the cyclin family.Cyclin B is a mitotic cyclin. The amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B...

-cdc2 complex activation causes breakdown of nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...

 and initiation of prophase
Prophase
Prophase, from the ancient Greek πρό and φάσις , is a stage of mitosis in which the chromatin condenses into a highly ordered structure called a chromosome in which the chromatin becomes visible. This process, called chromatin condensation, is mediated by the condensin complex...

, and subsequently, its deactivation causes the cell to exit mitosis.

Inhibitors



Two families of genes, the cip/kip family (CDK interacting protein/Kinase inhibitory protein) and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

 formation, they are known as tumor suppressors.

The cip/kip family includes the genes p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...

, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor β (TGF β), a growth inhibitor.

The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf
P14arf
p14ARF is an alternate reading frame product of the CDKN2A locus. Both p16INK4a and p14ARF are involved in cell cycle regulation. p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote...

 which prevents p53 degradation.

Synthetic inhibitors of Cdc25
Cdc25
Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...

 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.

Transcriptional Regulatory Network


Evidence suggests that a semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle. Several gene expression studies in Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

 have identified approximately 800 to 1200 genes that change expression over the course of the cell cycle; they are transcribed at high levels at specific points in the cell cycle, and remain at lower levels throughout the rest of the cell cycle. While the set of identified genes differs between studies due to the computational methods and criterion used to identify them, each study indicates that a large portion of yeast genes are temporally regulated.

Many periodically expressed genes are driven by transcription factors that are also periodically expressed. One screen of single-gene knockouts identified 48 transcription factors (about 20% of all non-essential transcription factors) that show cell cycle progression defects. Genome-wide studies using high throughput technologies have identified the transcription factors that bind to the promoters of yeast genes, and correlating these findings with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression. The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression).

Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando et al. used microarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1
G1
G1, G01, G.I or G-1 can be:-Sports:* G1 Climax, an annual professional wrestling singles tournament held by New Japan Pro Wrestling-Science:* G1 phase in the cellular cycle* G1 regulatory sequence for the insulin gene...

 and S phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...

. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events. Other work indicates that phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

, a post-translational modification, of cell cycle transcription factors by Cdk1
Cdk1
Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....

 may alter the localization or activity of the transcription factors in order to tightly control timing of target genes (Ubersax et al. 2003; Sidorova et al. 1995; White et al. 2009).

While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded mRNA.

Checkpoints


Cell cycle checkpoint
Cell cycle checkpoint
Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase...

s are used by the cell to monitor and regulate the progress of the cell cycle. Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met.

Several checkpoints are designed to ensure that damaged or incomplete DNA is not passed on to daughter cells. Two main checkpoints exist: the G1/S checkpoint and the G2/M checkpoint. G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point
Restriction point
The restriction point is a G1 phase checkpoint in the cell cycle of animal cells. Prior to the restriction point, a cell exits the cell cycle if specific mitogenic and growth signals are absent. Cells that progress past the restriction point are committed to enter S phase, where DNA synthesis and...

. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint
Postreplication checkpoint
-Postreplication checkpoint:When the genomic DNA of eukaryotic cells becomes damaged by spontaneous processes, chemical mutagens, or sunlight exposure, the replication of damaged DNA triggers a cellular response called a postreplication checkpoint...

.

p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints.

Role in tumor formation


A disregulation of the cell cycle components may lead to tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

 formation. As mentioned above, some genes like the cell cycle inhibitors, RB
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...

, p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 etc., when they mutate, may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 or radiation. This fact is made use of in cancer treatment; by a process known as debulking
Debulking
Debulking is the surgical removal of part of a malignant tumour which cannot be completely excised, so as to enhance the effectiveness of radiation or chemotherapy. It is used only in specific malignancies, as generally partial removal of a tumor is not considered a worthwhile intervention...

, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle.

The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.

In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S.

For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1

The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural radioprotectors and tend to be at their highest levels in S and at their lowest near mitosis.

Synchronization of cell cultures


Several methods can be used to synchronise cell cultures
Cell synchronization
Cell Synchronization is a process by which cells at different stages of the cell cycle in a culture are brought to the same phase. "Cell synchrony" is required to study the progression of cells through the cell cycle...

 by halting the cell cycle at a particular phase. For example, serum starvation and treatment with thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...

 or aphidicolin
Aphidicolin
Aphidicolin is defined as a tetracyclic diterpene antibiotic with antiviral and antimitotical properties. Aphidicolin is a reversible inhibitor of eukaryotic nuclear DNA replication. It blocks the cell cycle at early S phase...

 halt the cell in the G1 phase, mitotic shake-off, treatment with colchicine
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...

 and treatment with nocodazole
Nocodazole
Nocodazole is an anti-neoplastic agent which exerts its effect in cells by interfering with the polymerization of microtubules. Microtubules are one type of fibre which constitutes the cytoskeleton, and the dynamic microtubule network has several important roles in the cell, including vesicular...

 halt the cell in M phase and treatment with 5-fluorodeoxyuridine halts the cell in S phase. In addition, partial cell division cycle synchrony can be achieved in budding yeast as a consequence of metabolic synchrony. This metabolic synchrony at the level of synchronized cultures is an emergent, self-organized phenomenon based on a single-cell autonomous cell growth cycle taking place in the G1 phase of the cell division cycle.

See also

  • Cell cycle mathematical model
  • Cell cycle analysis
    Cell cycle analysis
    Cell cycle analysis is a method in cell biology that employs flow cytometry to distinguish cells in different phases of the cell cycle. Before analysis, the cells are permeabilised and treated with a fluorescent dye that stains DNA quantitatively, usually propidium iodide...

  • Mitosis
    Mitosis
    Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...

  • Meiosis
    Meiosis
    Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....

  • Interphase
    Interphase
    Interphase is the phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division. In preparation for cell division, it increases its size and makes a copy of its DNA...

  • Autoradiography -- Used to determine the duration of each phase of the cell cycle.
  • Biochemical Switches in the Cell Cycle
    Biochemical switches in the cell cycle
    A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases...

  • Cdc25
    Cdc25
    Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...


External links