THE CELL CYCLE AND PROGRAMED CELL DEATH

THE CELL CYCLE AND THE CELL CYCLE AND PROGRAMED CELL DEATH PROGRAMED CELL DEATH

The minimum set of processes that a cell has to perform are those that allow it to pass on its genetic information to the next generation of cells

Molecular Biology of Molecular Biology of CancerCancer 11

Molecular Biology of CancerMolecular Biology of Cancer22

Universal characteristics of cell cycleUniversal characteristics of cell cycle

The two major phases of the cell cycle The two major phases of the cell cycle Molecular Biology of CancerMolecular Biology of Cancer33

The eucaryotic cell cycle is traditionally The eucaryotic cell cycle is traditionally divided into four sequential phasesdivided into four sequential phases

Two functional phases, S and M phases Two preparatory phases, G1 and G2


Two functional phases, S and M Two functional phases, S and M phasesphases

S phase: The phase in which the DNA is replicated. The time it takes a typical human cell to complete S

phase is about 8 hours and is invariant under normal circumstances.

M phase: Fully replicated chromosomes are segregated to each

of the two daughter nuclei by the process of mitosis. The length of M phase is about 1 hour and is also

normally invariant.


Two preparatory phases, G1 and G2 Two preparatory phases, G1 and G2

G1 phase precedes S phase, whereas G2 phase precedes M phase.

G1 and G2 phases are required for the synthesis of cellular constituents needed to support the following phase and ultimately to complete cell division.

In mammalian cells, the length of G1 phase is highly variable and can range from about 6 hours to several days or longer.

The length of G2 phase is about 2 hours.


Two preparatory phases, G1 and G2 Two preparatory phases, G1 and G2

The cell monitors the internal and external environment When conditions are suitable and preparations are

complete the cell commits itself to S or M phase. If extracellular conditions are unfavourable:

cells delay progress through G1 and may even enter a specialized resting state known as GG 00 (G zero). (G zero).

Such cells are metabolically active, but are not actively proliferating.

If extracellular conditions are favourable: cells in early G1G1 or G0G0, become committed to DNA

replication, even if the extracellular signals that stimulate cell growth and division are removed


CELL-CYCLE CONTROLCELL-CYCLE CONTROL

A successful cell division cycle requires the orderly and unidirectional transition from one cell-cycle phase to the next.

Certain events must be completed before others are begun. For example, beginning mitosis before the completion of

DNA replication would obviously be deleterious to the cell.


Two classes of cell cycle regulatory Two classes of cell cycle regulatory circuits existcircuits exist

1. Intrinsic regulatory pathways: Responsible for the precise

ordering of cell-cycle events. for example, entry into mitosis must

always come after DNA replication.

A clock, or timer, that turns on each event at a specific time

It provides a fixed amount of time for the completion of each event.

Predominate in the transitions between S, G2, and M phases in mammalian cells because there time is relatively invariant.


Deregulation of intrinsic regulatory Deregulation of intrinsic regulatory pathways can contribute to cancerpathways can contribute to cancer

For example, errors in the spindle-assembly checkpoint can lead to chromosomal imbalance and aneuploidy, a feature characteristic of virtually all cancers.

Misregulation of proteins that control this checkpoint has been detected in human cancer


Two classes of cell cycle regulatory Two classes of cell cycle regulatory circuits existcircuits exist

2. Extrinsic regulatory pathways:

Function in response to environmental conditions or in response to detected cell-cycle defects.

In these pathways, differences between normal and neoplastic cells are most commonly observed.


The cell cycle control system is a The cell cycle control system is a protein kinase based machineprotein kinase based machine

The cell cycle control system is based on two families of proteins:

1.1. Cyclin-dependent protein kinase (Cdk)Cyclin-dependent protein kinase (Cdk) Selectively phosphorylates downstream

proteins on serines and threonines

2. The specialized activating proteins (cyclins)(cyclins) They bind to CdkCdk molecules and control

their ability to phosphorylate target proteins

They undergo a cycle of synthesis and degradation in each division cycle of the cell


Classes of cyclinsClasses of cyclins::1.1. G1/S-cyclinsG1/S-cyclins bind CdksCdks at

the end of G1G1 and commit the cell to DNA replication.

2.2. S-cyclinsS-cyclins bind CdksCdks during SS phase and are required for the initiation of DNA replication.

3.3. M-cyclinsM-cyclins promote the events of mitosis.

4. In most cells, a fourth class of cyclins, the G1-cyclinsG1-cyclins, helps promote passage through Start or the restriction point in late G1.


Classes of Classes of Cdk protein Cdk protein

In yeast cells A single CdkCdk protein binds all classes of cyclinscyclins

It drives all cell-cycle events by changing cyclin partners at different stages of the cycle.

In vertebrate cells, by contrast, there are four Cdks.

Two interact with G1-cyclinsG1-cyclins One interacts with G1/S-G1/S- and S-cyclinsS-cyclins One interacts with M-cyclinsM-cyclins.


The names of the individual Cdks and cyclinsThe names of the individual Cdks and cyclinsMolecular Biology of CancerMolecular Biology of Cancer1515

CYCLIN-CDKCYCLIN-CDKCOMPLEXCOMPLEX

VERTEBRATESVERTEBRATES BUDDING YEASTBUDDING YEAST

CYCLINCYCLIN CDK PARTNERCDK PARTNER CYCLINCYCLIN CDK PARTNERCDK PARTNER

GG11-Cdk-Cdk cyclin D* Cdk4, Cdk6 Cln3 Cdk1**

GG11/S-Cdk/S-Cdk cyclin E Cdk2 Cln1, 2 Cdk1

S-CdkS-Cdk cyclin A Cdk2 Clb5, 6 Cdk1

M-CdkM-Cdk cyclin B Cdk1** Clb1, 2, 3, 4 Cdk1

* There are three D cyclins in mammals (cyclins D1, D2, and D3).

Regulation of Cdk activity at different Regulation of Cdk activity at different stages of cell cycle:stages of cell cycle:


Phosphorylation/Dephosphorylation at a Phosphorylation/Dephosphorylation at a pair of aa in the roof of the active site:pair of aa in the roof of the active site:


• This regulatory mechanism is particularly important in the control of M-M-CdkCdk activity at the onset of mitosis.

Cdk inhibitor proteins (CKIs) bind to and Cdk inhibitor proteins (CKIs) bind to and regulate Cyclin-Cdk complexesregulate Cyclin-Cdk complexes


• There are a variety of CKICKI proteins that are primarily employed in the control of G1G1 and SS phase.

The Cell-Cycle Control System Depends The Cell-Cycle Control System Depends on Cyclical Proteolysison Cyclical Proteolysis

Two ubiquitin ligases are important in the destruction of cyclins and other cell-cycle regulators:

1.1. SCFSCF enzyme complex responsible for the ubiquitylation ubiquitylation and destructionand destruction of:

– G1/S-cyclins G1/S-cyclins and certain CKI proteinsCKI proteins that control S-phaseS-phase initiation

2.2. The anaphase-promoting complex (APCThe anaphase-promoting complex (APC) ) In M phase, is responsible for the ubiquitylation and proteolysisubiquitylation and proteolysis of:

– M-cyclins and M-cyclins and other regulators of mitosisregulators of mitosis




THE CELL CYCLE AND PROGRAMED CELL DEATH

Documents

cellcycle phase

g2 molecular biology

g2 g1 phase

cell growth

length of g1 phase

length of g2 phase

complete s phase

g2 phases