10. the cell cycle abc 2009

8/10/2019 10. the Cell Cycle ABC 2009

1/40

The Cell CycleMitosis

Tbilisi State Medical UniversityDepartment of Medical Biology and Parasitology

Gocha Shatirishvili2009


2/40

The Cell Cycle

Self-reproduction is one of the mostfundamental characteristic of cells

Each parental cell giving rise to twodaughter cells

Repeated cycles of cell growth and division -development of a single fertilized egg intothe more than 10 14 cells of human body


3/40


4/40

The Eukaryotic Cell Cycle

1.

Cell growth

2. DNA replication

3. Distribution of the duplicatedchromosomes to daughter cells

4. Cell division


5/40

Phases of the Cell Cycle: Mitosis and Interphase Mitosis (nuclear division) - separation of daughter

chromosomes and cell division - cytokinesis

Mitosis and cytokinesis last only about an hour

Interphase the period between mitoses

During interphase the chromosomes aredecondensed and distributed throughout thenucleus and cell growth and DNA replicationoccur
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886


6/40

The cell grows at a steady ratethroughout interphase

DNA is synthesized during onlya portion of interphase

The timing of DNA synthesis

thus divides the cycle ofeukaryotic cells into fourdiscrete phases


7/40

The M phase - mitosis

G1 phase (gap 1), the interval

between mitosis and initiation ofDNA replicationcell is metabolically active GrowthNo DNA replicatation

S phase (synthesis) - DNAreplication

G2 phase (gap 2), cell growth,proteins synthesis -preparation

for mitosis


8/40

Human cell with a total cycle time of 24 hours, theG1 phase about 11 hours, S phase - 8 hours, G2 - 4hours, and M - 1 hour

Cell cycles of early embryo cells shortly afterfertilization - 30 minutes no cell growth , divisioninto smaller cells, no G1 or G2 phase, DNAreplication occurs very rapidly =very short Sphases alternating with M phases


9/40


10/40


11/40

Cells at different stages of cell cycle can be distinguished by DNAcontent

G1 - containing two copies of each chromosome (diploid) S phase , replication increases the DNA content of the cell

from 2 n to 4 n

DNA content then remains at 4 n for cells in G2 and M,decreasing to 2 n after cytokinesis Cellular DNA content is determined by fluorescent dye that

binds to DNA, followed by analysis of the fluorescenceintensity of individual cells in a flow cytometer


12/40

B lymphoma cells in S and G2/M phases

f


13/40

Regulation of the Cell Cycleby Cell Growth and

Extracellular Signals

Cell cycle isregulated byextracellular signals (growth factors) fromthe environment, as

well as by internalsignals

Cell growth, DNAreplication, andmitosis, arecoordinated by aseries of controlpoints


14/40

Restriction Point Cells enter in the cell cycle is

regulated primarily by the

extracellular growth factors thatsignal cell proliferation

Decision point in late G1, called therestriction point in animal cells

Restriction point is the point at whichcell growth is coordinated with DNAreplication and cell division.

In the presence of theappropriate growth factors ,cells pass the restriction point and enter S phase
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886


15/40

Once cell has passed through the restriction point,

the cell enter in S phase, even in the absence offurther growth factor stimulation

If appropriate growth factors are not available inG1, progression through the cell cycle stops at therestriction point

Such arrested cells then enter a quiescent stage ofthe cell cycle called G0, in which they can remainfor long periods of time without proliferating.

G0 cells are metabolically active, although theycease growth and have reduced rates of proteinsynthesis


16/40


17/40

Some cell cycles are controlled inG2: oocytes

Vertebrate oocytes can remain

arrested in G2 for long periods oftime (several decades in humans ) until their progression to M phase is

triggered by hormonal stimulation


18/40

C ll l h k i t th t i l t


19/40

Cell cycle checkpoints ensure that incomplete ordamaged chromosomes are not replicated andpassed on to daughter cells

G2 checkpoint prevents the initiation of mitosis

until DNA replication is completed.


20/40


21/40


22/40

Loss of p53 function as a result of thesemutations prevents G1 arrest in response toDNA damage

Damaged DNA is replicated and passed onto daughter cells instead of being repairedand results cancer development.

Mutations in the p 53 gene are the mostcommon genetic alterations in humancancers

C li g f S Ph t M


23/40

Coupling of S Phase to MPhase

DNA replication is restricted to

once per cell cycle by MCMproteins that bind to origins ofreplication of DNA together withORC (origin replication complex) proteins in G1, allowing DNA

replication to initiate in S phase

Once initiation has occurred, theMCM proteins are displaced andreplication cannot initiate again

until after mitosis

These controls prevent cells in G2from reentering S phase

.

Th E t f M Ph


24/40

The Events of M Phase-Mitosis (nuclear

division)1. Chromosome condensation

2. Formation of the mitoticspindle

3. Attachment of chromosomesto the spindle microtubules

4. Sister chromatids separationfrom each other and move to

opposite poles of the spindle

5. Formation of daughter nuclei

6. Cell division


25/40


26/40


27/40

Mitosis


28/40

P h


29/40

Prophase The appearance of

condensed chromosomes

The condensed sisterchromatids are held togetherat the centromere , DNAsequence to which proteinsbind to form the

kinetochore the site ofeventual attachment of thespindle microtubules

The centrosomes incytoplasma separate andmove to opposite sides ofthe nucleus

They serve as the two polesof the mitotic spindle

Prometaphase
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cooper.glossary.2886


30/40

Prometaphase Prometaphase-

transition period

between prophaseand metaphase.

Duringprometaphase themicrotubules of themitotic spindle attach to thekinetochores ofcondensedchromosomes.


31/40

Metaphase and Anaphase Breakage of

the link

between sisterchromatids,separation andmove toopposite polesof the spindle

T l h N l i f d


32/40

Telophase Nuclei re-form andthe chromosomesdecondense

Cytokinesis beginsduring lateanaphase and isalmost completeby the end oftelophase-

formation of twointerphasedaughter cells


33/40

The condensation


34/40

The condensationof interphasechromatin a

thousand fold Protein complexes

-condensins causecondensation bywrapping DNAaround itself

The condensinsare phosphorylateddirectly by theCdc2 proteinkinase

Breakdown of the nuclear envelope


35/40

Breakdown of the nuclear envelope

Cdc2 phosphorylates the lamins depolymerization of nuclear lamina andfragmentation of the nuclear membrane

These fragments form new daughter nuclei at

telophase

The endoplasmic reticulum and Golgi apparatus


36/40

The endoplasmic reticulum and Golgi apparatusfragment into small vesicles, which are bedistributed to daughter cells at cytokinesis .

Golgi matrix protein GM130 is p hosphorylated byCdc2 , leading to fragmentation of the Golgi apparatus.

MPF activity induces a depolymerization andshrinkage of the interphase microtubules byphosphorylation of microtubule-associatedproteins

Interphase microtubules are replaced by largenumbers of short microtubules radiating from thecentrosomes


37/40

Proteolysis and theInactivation of MPF

After completion of mitosis MPF is degraded byubiquitin-mediated proteolysis , triggered byubiquitin ligase : anaphase-promotingcomplex

Activation of the anaphase-promotingcomplex is induced by MPF at the beginningof mitosis - MPF ultimately triggers its owndestruction


38/40

Activation of the anaphase


39/40

Activation of the anaphase-promoting complex leadsto the degradation of atleast two key regulatoryproteins : Scc1 , acomponent of a complex of

proteins called cohesins (that maintain theconnection between

sister chromatids ) viadegradation of of Pds1 andactivation Esp1

C yclin B -targeted for


40/40

C yclin B targeted forubiquitination anddegradation by the anaphase-promoting complex

Degradation of cyclin Bleads to inactivation of MPF and cell to exit mitosis andreturn to interphase.

Reassembly of the nuclearenvelope

Chromatin decondensation The return of microtubules to

an interphase state are resultof MPF activity loss

10. the cell cycle abc 2009

Documents