the cellular cycle is the whole of the phases by which a cell passes between two successive divisions.

Durations

They could be measured In vitro in optimal conditions:

• At the Procaryotic S (Bacterium S): 20 minutes

• At the Eucaryote S:
• Yeast: 2 hours
• Fibroblast S human 16 to 12 midnight.

Phases of the cellular cycle

Introduction: The notations quantitatives'

The Génome of the Eucaryote S superiors includes/understands a number NR of the types of Chromosomes. This number differs from one species to another.

Each cell Diploïde contains two homologous chromosomes (having the same functions) per type - one coming from the father and one coming from the mother - on the whole 2 times NR, shortened " 2N" , chromosomes.
Each cell Haploïde contains only one chromosome per type - a mixture of genes of the father and the mother obtained by the process of " cross-country race-over" , to see below - on the whole 1 time NR, shortened " 1N" chromosomes. The chromosomes produced by the process of replication are called " chromatides" or " chromatides-sœurs" and do not take again their name of " chromosome" that after their separation in mitosis/anaphase or meiosis/anaphase2. Other sources do not use the term " chromatide" that as from the moment when the centromères of the chromosomes are in contact one with the other.

The number of Chromatide S by type of chromosome in a cell is indicated by a figure, follow-up of the letter C. For example, " 4C" for 4 chromatides by type of chromosome.

Some examples:

• a cell diploïde to two chromatides (before the phase S and in mitosis: telophase) will thus be noted: " 2N-2C"
• a cell diploïde to four chromatides (mitosis: prophase with anaphase): " 2N-4C"
• a haploid cell with two chromatides (meiosis: télophase1 with anaphase2): " 1N-2C"
• a haploid cell with a chromatide (meiosis: télophase2): " 1N-1C"

Note: By preoccupation with a clearness, the illustrations and the texts which follow are written as if there existed only one type of chromosomes. It should obviously be retained that they apply to the whole of the NR types of chromosomes.

Interphase

It is the whole of the phases between two successive cellular divisions:

• G0 (2N-2C), " G" for " gap" or " growth" , known as phase of quiescence. The cell left the cellular cycle. The majority of the cells differentiated constituting fabrics from an adult organization are in this phase. There is not generally regeneration of the bodies. The cells in G0 phase can return in G1 phase under the influence of Antigène S, Hormone S or growth factors.

• G1 (2N-2C): First phase of cell multiplication (without replication nor division). The duration of the G1 phase is variable (90 minutes to several days). Certain cells have a very short G1 phase. It is the case for egg fertilized during the Blastulation.

• S (passage to 2N-4C): " S" for " synthèse" of DNA. Phase corresponding to the replication of DNA. The chromosomes are retorted so that the Génome of the cell mother can be also distributed in the cells girls (diploïdes or haploid). The bits of each chromosome are separated by cut from the Hydrogen bonds. In the same tread, a new chromosome (or chromatide) is rebuilt on each bit by contribution of the complementary bases. The duration is of approximately 8 hours. Each chromosome is thus replaced by two chromatides sisters.

• G2 (2N-4C): Second phase of cell multiplication. The duration is from 3 to 4 a.m.

• M : The cellular phase of division. The somatic cells divide by Mitose whereas the germinal cells (Spermatogonie S and Ovogonie S), divide by Méiose.

Mitosis

The goal of the mitosis is primarily with the growth - by replication and cellular division - fabrics of the bodies of the organization. This growth goes hand in hand with cellular differentiation.

During mitotic division, the cell mother gives rise to two cells genetically identical girls. One of the cells girls remains at the stage of differentiation of the cell mother, whereas the other passes at a later stage of differentiation. A fabric is thus consisted a whole of cells more or less differentiated according to the number of divisions with differentiation in its line. For example, the original cells are the product of lines without differentiation, whereas the highly differentiated cells come from lines including/understanding a great number of differentiations. The fairly differentiated cells represent the majority.

• Prophase (2N-4C): During the prophase, the chromatides sisters, which until now appeared in the form of filaments dispersed in the core, condense and form pairs of sticks connected to each other to the level of the Centromère. The envelope of the core dissolves and two Centriole S give an opinion at the two ends of the cell, from which they project Microtubule S towards the center of the cell, forming the Fuseau mitotic. The microtubules Kinétochore S stick to the chromatides on the level of the kinétochores, structures rich in proteins, close to the centromères.

• Metaphase (2N-4C): The microtubules position the chromosomes on the equatorial level of the cell by their mechanical movements: the microtubules kinétochores narrow by dismantling and removal of modules on the level of the kinétochore and the microtubules non-kinétochores lengthen by addition of modules on the level of the equatorial plan. This stage, one with the possibility of carrying out the chromosomic chart thanks to the great condensation of the chromosomes.

• Anaphase (2N-4C): Always under the effect of the microtubules kinétochoriens, the centromères tear and the chromatides sisters separate and migrate in direction opposed towards the centrioles. One thus finds at the ends of the cell of the pairs of what are become again of the " chromosomes homologs" , coming from different parents. There is an elongation of the polar microtubules which lengthen the cell

• Telophase (2N-2C): A nuclear envelope is formed at the two ends of the cell, around the chromosomes which regain their filamentous shape. The cell divides by Cytokinèse. The homologous chromosomes respectively find in one of the two cells girls (of return in phase G0 or G1) .disparition of the microtubules kinétochoriens, reappearance of the nucleole, the apparatus of golgi as of the endoplasmic reticulum which separated in two equal quantities

Meiosis

The goal of the Méiose is double: on the one hand the mixture of the Genome paternal and maternal, thus ensuring a maximum genetic variation, and on the other hand production of haploid cells to a chromatide for the sexuée reproduction.

• Prophase 1 (2N-4C): As for the prophase of the mitosis one has at the beginning a pair of chromatides paternal sisters and a pair of chromatides maternal sisters. It is at this stage that the " occurs; crossing-over" allowing the mixture of the maternal and paternal genome. Until now the chromosomes of the father and the mother were côtoyaient. Now they are linked. During the process called " synapse" , the chromatides are aligned side by side. The homologous chromatides form chiasmes (crossings) on the level of which segments of chromatide are exchanged and recombined by successive cuts and joinings.

• Metaphase 1 (2N-4C): The pairs of chromatides are aligned on the equatorial level of the core. As for the mitosis, a spindle of microtubules is formed starting from the poles of the core. Microtubules kinétochores stick to the kinétochores each chromatide. The nuclear envelope dissolves.

• Anaphase 1 (2N-4C): The two pairs of chromatides are attracted each one towards a pole of the cell. At this stage only the pairs of chromatides are separate but not the chromatides sisters themselves.

• Telophase 1 (1N-2C): A new nuclear envelope is formed around the respective pairs of chromatides, forming two haploid cores, containing each one only one pair of chromatides. This division is called " réductionnelle" because it implies a passage of diploïde to haploid. The cell divides in its turn by cytokinèse.

• Prophase 2 (1N-2C): Each haploid cell formed at the time of telophase 1 contains a pair of chromatides of maternal or paternal origin, but whose genes consist of mixed elements following the " crossing-over".

Small easy way to remember about the 4 phases: retain this sentence well: For My Love Always (P--> prophase; M--> metaphase; With--> anaphase; T--> telophase).

the text which follows applies to each of the two above-named haploid cells.

• Metaphase 2 (1N-2C): As at the time of the mitotic metaphase, the spindles of microtubules are formed and maintain the centromères chromatides on the level of the equatorial plan.

• Anaphase 2 (1N-2C): Contrary to division " réductionnelle" anaphase 1 which separates two pairs from chromatides, division " équatoriale" anaphase 2 separates the chromatides sisters, as in the anaphase of the mitosis.

• Telophase 2 (1N-1C): A nuclear envelope is reformed around each of both chromatides and the cell divides giving rise to two cells, always haploid, but containing each one only a chromatide.

At the time of fecundation a cell 1N-1C will amalgamate with a gamète of another organization to produce a zygote 2N-2C.

Mechanisms of regulation

Legend:

• ATP: " TriPhosphate" adenosine;
• ADP: " DiPhosphate" adenosine;
• Cdk: " Cyclin-depend Kinase"
• CKi: " Cyclin-depend Kinase inhibiters"
• CAK: " Cdk Activating Kinase"
• Chk1: " Checkpoint1"
• Chk2: " Checkpoint2"
• " p" followed by a figure " means; protéine" , p.ex. p21: " protein 21"

The Cdk-Cycline complexes

Structure and functions

The mechanisms of the regulation of the cellular cycle are contingent primarily on two called complementary proteinic structures Cdk (" Cycline-depend kinase") and cycline. Cdk is the basic component, but, as its name indicates it, it needs a cycline to activate its functions. Cdk and the cyclines join and form complexes hetero-dimeric.

There exist several kinds of Cdk and cyclines. The first are identified by figures and the seconds by letters. For a complex one will note, for example: Cdk4-CyclineD. Cdk can form complexes with several cyclines different and conversely. To each phase of the cellular cycle one or more complexes Cdk- cycline correspond.

Cdk consists of two lobes: the lobe NR, primarily consisted of layers beta and the lobe C, primarily consisted of propellers alpha.

With the intersection of the two lobes is a catalytic site where the Phosphorylation occurs which activates proteins playing a part in the cellular cycle (the fragmentation of the nuclear envelope, compaction of the chromosomes, the replication of the DNA, etc). The site includes/understands two juxtaposed pockets: one to accommodate the substrate (the protein with phosphoryler), the other to receive ATP. In substance, the phosphorylation is done by transfer of phosphate-γ of the ATP towards the substrate. Resulting ADP is then slackened.

In an inactive state, the entry of the catalytic site is blocked by two protein loops: field PSTAIRE (named thus according to the initial ones of the constituent amino-acids) and buckles it T (" T-loop").

During association with the cycline, loop PSTAIRE undergoes a rotation which works pocket ATP in order to obtain an adequate orientation of the triphosphate at the time of phosphorylation of the substrate.

At the same time, the loop T is moved, which exposes certain amino-acids of the CDK (the Thréonine 161, the Thréonine 14 and the Tyrosine 15) to regulating kinases.

The cyclines are the paramount activators of the complexes Cdk- cycline. Moreover, they are controlled by a number of kinases and phosphatases activatrices and inhibiting, as by inhibiting molecules called the CKI (cyclin-depend kinase inhibiter).

Kinases activatrices

• CAK, by phosphorylant the thréonine 160 exposed to the top of the loop T, induced a reconfiguration of the loop which makes the pocket substrate accessible. It however seems that the regulating effect of CAK is negligible, since its concentration is maintained with an elevated level and constant during all the cellular cycle. On the other hand, Cak would play a crucial role in the regulation of the transcription by the ARN polymerase II.

CAK is defined like " Cdk-activated kinase" in the hat " abréviations": in fact it is a " Cdk-activating" kinase.

Phosphatases activatrices

• Cdc25 phosphatases, by déphosphorylant the amino-acids thréonine 14 and tyrosin 15, allow the access to pocket ATP and the activation of the complexes Cdk- cyclines. At the man, the Cdc25 family comprises various members specialized by transition from the cycle:
• Cdc25A for G1-S and G2-M
• Cdc25B and Cdc25C primarily for G2-M

Inhibiting kinases

• Wee 1, by phosphorylant tyrosin 15, prevents the access to pocket ATP. Myt1 plays the same part, but for tyrosin 15 and thréonine 14 at the same time.
• Chk1 and Chk2 inhibits Cdk1-CyclineB:
• by sequestration of CDC25 in the cytoplasm, far from Cdk1-CyclineB which is not thus activated any more
• by inhibition of PoloK which ceases activating Cdc25 which thus does not activate any more Cdk1-CyclineB
• ATR (kinase " Ataxia-Telangiectasia Related" , related to the DNA), Cdk1-CycineB via Chk1
• ATM (kinase " inhibits; Ataxia-Telangiectasia Mutated" , related to the DNA), via Chk2, P53 activates, which activates p21, which inhibits Cdk1-CyclineB

Inhibiters (CKI)

• CKi p16, while joining Cdk4 and Cdk6, prevents the connection with the cycline D.
• CKi p21, on which the transcription is dependant on p53, inhibits Cdk2-CyclineE, Cdk2-CyclineA and Cdk1-Cycline B
• by association with the cycline, which blocks pocket ATP
• by decreasing the rate of CAK

Processes of regulation

The transition from G0 to G1

At the time of the transition place has the transcription of essential genes for G1 and the entry in division. This transcription is stimulated by two ways of indication:

• Of the growth factors, via transmembrane receivers of the type tyrosin kinase as well as stimuli mitogenes, via receivers coupled to proteins G, starts cascades of the MapKKK/MapKK/MapK type, which stimulate the gene transcription such as CyclineD and Cdk4&6.
• a dimer consisted the proteins Myc and max activates the transcription of genes of Cdc25A, Cdk4, Cdk6, CyclineD, CyclineE, E2F.

The G1 phase

The genes of the cyclines D and E as well as the proteins p21 and p27 are transcribed, of which cyclineE under the control of E2F.

The passage of G1 with S

This passage is under the control of the point R, itself under the control of several proteins: Rb, E2F, cdk2, cdk4. In G1, Rb not phosphoryl binds to E2F and inhibits it. During the passage cycD/cdk4 and cycE/cdk2 hyperphosphorylent Rb, which releases E2f. Free E2F induced its target genes and allows the progression of S.

The passage of the G2 phase with M

This passage is controlled by the CDK1-CyclineB complex.

At the beginning, the cycline B is fixed at Cdk1 which will cause " the ouverture" arm giving access to the site ATPasique de Cdk1. The complex cycline B-Cdk1 will be phosphoryl by the Wee1 enzyme on the Thréonine 14 and the Tyrosine 15 of Cdk1 which prevents the access of ATP to the ATPasique site.

Then, enzyme CAK phosphoryl the complex on the thréonine 160 of Cdk1 which allows " the ouverture" arm giving the substrate access to the site substrate of Cdk1. Since the access to site ATP is blocked, Cdk remains inactive, therefore phosphoryler yet the substrate cannot. At this stage, the complex is phosphoryl 3 times. That forms the preone.

So that this last becomes active and thus induces the passage in Mitose, it must be déphosphorylé on residues 14 and 15 by Cdc25: that causes " the ouverture" arm giving access to the ATPasique site. Indeed, the complex phosphoryl only on residue 161 of Cdk1 forms the active MPF.

The ATP with the ATPasique site yields its grouping phosphates with the substrate which is thus phosphoryl. According to the nature of the substrate, this phosphorylation will inhibit or activate this substrate.

There is thus a true competition between Wee1 which is a kinase and which thus will have tendency to phosphoryler on residues 14 and 15 and thus inactiver the MPF; and Cdc25 which is a phosphatase and which thus will tighten with déphosphoryler residues 14 and 15 and thus will activate the preone in active MPF. It entered there in phase of mitosis.

It is noted that Wee1 is active when it is not phosphoryl, whereas Cdc25 is active only when it is phosphoryl. There is thus the intervention of other proteins Kinase and Phosphatase.

Measure

The percentage of cells of a population in each phase of the cycle can be counted in cytometry of flow.

Importance

The regulation of the cellular cycle must be very fine. For example, the Cancer S are characterized by an anarchistic proliferation due to the disordered state of the control system of the cellular cycle. See Oncogène S, which is often genes coding of proteins responsible for the control of the cellular cycle.

NB: At the time of the cellular cycle, there exist " points of contrôle" who allow the cell to check that no modification at the genetic level (incorrect replication of the DNA) and structural (spindle mitotic malformed) was not made. These systems are very important for the integrity of our genetic inheritance. These check-points can prevent the advance of the cycle if the conditions are not met and by this fact engage the cell in apoptose (cellular programmed death). These check-points can be faded and prevent any regulation of the cellular cycle.

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