Cell cycle seminar

CELL CYCLE

13/09/2014 1Cell cycle/B.Dutta/MBT/ 2014-2016

1. Introduction2. Phases of the cell cycle 3. G1 phase 4. S phase 5. G2 phase 6. Cyclin and cyclin- dependent kinesis7. Cell control ( check points ) 8. Stages of mitosis and meiosis9. Loss of control in Cancer Cells10. Recent work 11. Reference 13/09/2014 2Cell cycle/B.Dutta/MBT/ 2014-2016

The cell cycle is a sequence of cell growth and division.

The cell cycle is the period from the beginning of one division to the beginning of the next.

The time it takes to complete one cell cycle is the generation time.


Cell cycleBeginning of one division to beginning of nextStages in cell cycleInterphase

First gap phase (G1)Synthesis phase (S) Second gap phase (G2)

M phaseMitosis (M) Cytokinesis


The mammalian cell cycle consists of four discrete phases

S-phase : DNA is replicated M-phase : chromosomes are separated over two new nuclei in the process of mitosis.

These two phases are separated by two so called “Gap” phases, G1 and G2.



– Gap 1 (G1): cell growth and normal functions

– Gap 2 (G2): additional growth

– Mitosis (M): includes division of the cell nucleus (mitosis) and division of the cell cytoplasm (cytokinesis)

– DNA synthesis (S): copies DNA


During Go the cell decides to divide, die, or stay differentiated.

G1 phase: The cytoplasm increases in volume ( proteins,

carbohydrates and lipids are synthesized). Damage to the DNA is repaired. If the

nuclear DNA is damaged a protein called p53 increases in activity and stimulate p21 to arrest the cells in G1 phase. If the repair is failed the cell commits suicide.


The cell checks with the environment before entering S phase.

DNA synthetic enzymes activated, DNA replicated and centrioles begin to duplicate.

From end of S phase to mid of M phase has 23 chromosomal pairs.

G1 and G0 is the only phase of the cell cycle which 46 chromosomes corresponds to DNA molecules.

Lasts 8 hours


Completion of DNA synthesis checkedCell volume checked

M-phase cyclin dependent kinases ativatedCentrioles duplication completedThe second check point in cell size occurs in

G2 13/09/2014 10Cell cycle/B.Dutta/MBT/ 2014-2016

Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks)

The activity of cyclins and Cdks fluctuates during the cell cycle

Different Cyclins, specific for the G1-, S-, or M-phases of the cell cycle, accumulate and activate CDKs at the appropriate times.


Contain a homologous region of about 100 amino acids called the cyclin box and it is this region of the protein which binds to the appropriate CDK.

The cyclins are broadly classified into G1 and mitotic cyclins, according to the stage of the cycle during which they are produced.

Cyclin degradation results in CDK inactivation.


Four classes of cyclins:1. G1-cyclins—help to promote passage through“Start”or the restriction point in late G12. G1/S-cyclins—bind Cdks at the end of G1 andcommit the cell to DNA replication3. S-cyclins– binds Cdks during S phase and arerequired for the initiation of DNA replication4. M-cyclins—promote the events of mitosis


The CDKs are activated by forming complexes with cyclin partners

Are also activated by phosphorylation of a conserved threonine residue at position 160 and by cyclin binding.

E.g., Phosphorylation of the CDKs CDC2, CDK2 and CDK4 is carried out by the p40mol5 protein which in turn is activated by cyclin H


o 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.

o When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle.

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


The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock

The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is given


Each of the cyclin-CDK complexes, together with the CDKIs (CDK Inhibitors), are responsible for controlling different stages of the cell cycle by preventing progression through checkpoints in the presence of DNA damage.

Late G1 CheckpointThe D type cyclins are linked to the regulation of

the first checkpoint at G1/S.

Synthesized in response to growth factors and are very short lived.



For many cells, the G1 checkpoint seems to be the most important one

If a cell receives a go-ahead signal at the G1 checkpoint, it will usually complete the S, G2, and M phases and divide.

If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a non-dividing state called the G0 phase.

Hartwell and Weinert first defined the term cell cycle checkpoint as a mechanism that maintains the observed order of events of each cell cycle.



The E type cyclins are believed to act after the D type and to be important for the initiation of DNA replication

Cyclin E is expressed towards the end of G1, and complexes with CDK2 to activate it.

After cells have entered S phase, cyclin E is rapidly degraded and CDK2 is released to be complexed by cyclin A at the next stage.





Prophase:

Metaphase: Spindle fibers line the chromosomes along the middle of the cell nucleus.

Anaphase: The paired chromosomes separate at the kinetochores and move to opposite sides of the cell

Chromatin in the nucleus begins to condense and becomes visible in the light microscope as chromosomes.


Telophase: Chromatids arrive at opposite poles of cell, and new membranes form around the daughter nuclei.

Cytokinesis: results when a fiber ring composed of a protein called actin around the center of the cell contracts pinching the cell into two daughter cells, each with one nucleus.




Diploid cells undergo meiosis to form haploid cells

Meiosis potentially produces four haploid cells

Meiosis involves two separate divisions


Two successive nuclear divisions occur, Meiosis I (Reduction) and Meiosis II (Division).

Meiosis I reduces the ploidy level from 2n to n (reduction) while Meiosis II divides the remaining set of chromosomes in a mitosis-like process (division).



Cancer cells do not respond normally to the body’s control mechanisms

Cancer cells form tumors, masses of abnormal cells within otherwise normal tissue

If abnormal cells remain at the original site, the lump is called a benign tumor

Malignant tumors invade surrounding tissues and can metastasize, exporting cancer cells to other parts of the body, where they may form secondary tumors



C. elegans embryo,has asymmetric cell divisions which produce descendants whose cell cycle durations are different .

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1. They are using a model system of the nematode C. elegans, since this organism and proteomics. provides a powerful setting in which cell cycle control can be genetically analyzed during development by combining cell biology techniques

Specifically, they are investigating the role and regulation of Cullin-RING ubiquitin-ligases (CRLs) during C. elegans development. CRLs are the largest family of ubiquitin-ligases, and its members selectively target diverse protein substrates such as cell cycle regulators for ubiquitin-dependent degradation by the 26S proteasome.


2. Sir David of CYCLACEL company discovered the p53 protein, a key regulatory gene that malfunctions in about two-thirds of cancer patients. David Glover discovered several genes (Aurora and Polo kinases) that drive mitosis and that in mutated form are linked to many cancers.

Cyclacel Pharmaceuticals is developing a large pipeline of drugs that target multiple, distinct points in the cell cycle.

i. Introduction :

Molecular cell biology: Harvey Lodish 5th edition Pdf. Chapter 21. Page 844-848.

ii. Phases of cell cycle: Molecular cell biology Harvey Lodish , 5th Edition. Pdf. Chapter 21. Page 845-846.

iii. Regulation of cell cycle : R. Curtis Bird http://: www.mol-bio4 masters.grkraj.org ( 2.45pm, 8/09/14)


http://www.mol-bio4/


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iv. Role of cyclin and dependent kinases cyclin : R. Curtis Bird http://www.mol-bio4 masters.grakraj.org, www.landsbioscience.com/curie/chapt/1074 ( 3.00pm, 8/09/14 ) Coqueret O: Linking cyclins to transcriptional control.Gene. 2002 Oct 16;299(1-2):35-55v. Cell division : Harvey Lodish 5th Edition.Pdf Chapter 21, Page 846-848 vi. Cell cycle in cancer by Cyclacel www.cyclacel.com>research and development>science and technology. ( 2.19pm, 12/09/14) vii. Recent development by Cyclacel and Isnt. of Jacques Monod , www.ijm.fr/en/research/research-groups/cell-cycle -and-development. (3.00pm, 12/09/14).

http://www.mol-bio4/

http://www.landsbioscience.com/curie/chapt/1074

THANK YOU!!!


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Cell cycle seminar