By247 Cell Pathobiology Cell Cycle Control System

Front 1

Phosphorylation and dephosphorylation is one of the most common way to switch a protein on or off

Back 1

Phosphorylation - protein kinases

dephosphorylation - phosphatase

Front 2

Different Cyclin - CDK complexes trigger different steps in the cell cycle

Back 2

M cyclin - Acts in G2 to trigger entry into M phase

S cyclin and G1/S cyclins - bind to distinct CDK protein late in G1 (Help launch S-phase)

G1 cyclins - Acts earlier in G1 binds to other CDK proteins to form G1-CDK (Help drive the cell through G1 towards S phase

Front 3

The abrupt degradation of M and S cyclins part way through M Phase depends on a large enzyme complex

Back 3

Anaphase promoting complex (APC)

Tags the cyclins with an ubiquitin chain

Ubiquitinylation and degradation of the cyclin returns its CDK to an inactive state

Front 4

CDK Activity can be blocked by CDK inhibitor proteins

Back 4

Ink4 family (p15, 16, 18, 19) - inhibit CDK4 and 6

Cip/Kip family (p21, 27, 57) - inhibit CDK1/cyclin A, CDK1/cyclin B, CDK2/ cyclin A, CDK2/ cyclin E

Phosphorylation at a pair aof amino acids inhibits the activity of cyclin-CDK complex by protein kinase Wee1 and dephosphorylation by Cdc25 to increase CDK activity

Front 5

G1 phase

Back 5

High metabolic activity, cell growth and repair

If S-CDK and M-CDK are not disabled by the end of M phase, the cell will immediately replicate its DNA and initiate another round of division without spending time in G1 or G2

The CDK-cyclins are inhibited by blocking synthesis of new cyclins and CDK inhibitor proteins

Front 6

Negative Control Mediated by Rb (Retinoblastoma) protein

Back 6

Binds to transcription regulators and prevent them from turning on the genes required for cell proliferation

Mitogens release the Rb brake by triggering the activation of G1-Cdks and G1/S- CDK

The complexes phosphorylated Rb protein and altering its conformation so it releases its bound transcription regulators

Front 7

Cyclin D / CDK 4/6

Back 7

Responsible for initiating Rb phosphorylation

Initial hypophosphorylation of Rb is required but not sufficient to inactivated Rb (requires hyperphosphorylation, reach R-point

Cyclin E increase dramatically at R point (Cyclin E/CDK2 drive Rb phosphorylation to completion

Further increase by cyclin E, A and B

Front 8

P53

Back 8

DNA damage in G1 causes an increase in both the concentration and activity of a protein - p53

Transcription regulation that activates the transcription of a gene encoding a CDK inhibitor protein p21

P21 binds to G1/S-CDK and S-CDK, preventing them from driving the cell into S phase

The arrest of cell cycle in G1 gives the cell time to repair the damaged DNA

Front 9

S phase

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S-CDK initiates DNA replication and block re-replication

When DNA is made replication-ready by the recruitment of protein to the sites along each chromosome where replication begins (sequence = origins of replication)

Serve as landing pads for the proteins and protein complexes

ORC, origin recognition complex, remains perched atop the replication origins and recruits Cdc6

S-CDK is assembled and activated, it activates the DNA helicases in the prereplication compiles and promotes the assembly of the rest of the proteins that form the replication fork

Cdc25 is inhibited when DNA is damaged, preventing the removal of the inhibitory phosphates M-CDK remains inactive and M phase is delayed

Front 10

M-phase

Back 10

The central problem for a cell in M-phase is to accurately segregate the chromosomes that were duplicated in the preceding S-phase

M-CDK drives entry into M-phase and mitosis, helps prepare the duplicated chromosomes for segregation

M-CDK complex accumulate throughout G2, the activation is self-reinforcing, it activates cdc25 and shuts own Wee1

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Condensins

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Help carry out chromosome condensation

Reduce mitosis chromosomes to compact bodies that can be easily segregated within the crowded confines of the dividing cells

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Cohesins

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Duplicated chromosomes and associated proteins (sister chromatids) are held together by the protein complex

Assemble along the length of each chromatid as the DNA is replicated

Broken completely in late mitosis

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Different cytoskeleton assemblies carry out mitosis and cytokinesis, cytoskeletal machines assemble in sequence to carry out the two me archival processes in M phase

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Mitotic spindle carries out nuclear division (mitosis)

The contractile ring carries out cytoplasmic division (cytokinesis)

Both structures dissemble rapidly after they have performed their task

Front 14

Mitotic spindle

Back 14

Responsible for separating the duplicated chromosomes and allocating one copy of each chromosomes to each daughter cell

Front 15

Contractile ring

Back 15

Consists mainly of action filament sand myosin filaments Starts to assemble just beneath the plasmamembrane towards the end of mitosis

Front 16

APC triggers the separation of sister chromatids

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Triggers the cleavage of the cohesins

Catalysts the ubiquitinylation and destruction of an inhibitory protein called securin (targeted by APC)

When freed from securin, separate cleaves the cohesin complexes (allow spindle to pull chromatids apart)

Front 17

An unattached chromosome will prevent sister chromatids separation

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The cell use negative signal to monitor chromosome attachment

Unattached chromosomes send a stop signal to the cell cycle control system

By blocking the activation of cdc20-APC

Front 18

Early regulatory proteins trigger the transcription of cyclin D

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Regulatory proteins such as transcription factor Myc, Fos and Jun

Synthesis of cyclin D

It's synthesised later = delayed response gene expression

Front 19

Main target of cdk4 and 6/ cyclin D is Rb protein

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Frees E2F to act as a transcription factor on many S-phase genes, leading to cell cycle entry

Front 20

Mitogen-stimulated signalling via Myc

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Like Fos, Myc also stimulates cyclin D synthesis

stimulates E2F synthesis directly, as well as p27 degradation by increasing transcription of SCF

Front 21

The events of mitosis are controlled by M-phase CDK complex cdc2/ cyclin B

Back 21

Catalyses multiple phosphorylation events initiating several events required during (maturation promotion factor)

Front 22

Control of DNA damage checkpoints

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The G1 checkpoint is mediated by transcription factor - p53

Damaged DNA in G2 sends a signal to a series of protein kinase that phosphorylated and inactive ate the phosphatase Cdc 25

Blocking entry into mitosis