CELL DIVISION CYCLE Kanokporn Boonsirichai

TWO TYPES OF CELL DIVISION

Mitosis Chromosome number is preserved.

Meiosis Chromosome number is reduced by half.

MITOSIS

MEIOSIS

Crossing over

Meiosis does two things -

1) Meiosis takes a cell with two copies of every chromosome (diploid) and makes cells with a single copy of every chromosome (haploid).

2) Meiosis scrambles the specific forms of each gene that each sex cell (egg or sperm) receives.

Crossing over

Independent assortment

CONTROL OF CELL CYCLE

Figure 18-1 Essential Cell Biology (© Garland Science 2010)

Prokaryote: Escherichia coli ~ 20 minutes

Figure 18-2 Essential Cell Biology (© Garland Science 2010)

PHASES OF THE CELL CYCLE

CELL CYCLE CONTROL SYSTEM

A timer/clock: when and how long

A play list: ordering of event

Preventions of repeats On/off switches Backup mechanisms Adaptibility/sensors

CELL CYCLE CHECKPOINTS

Cause the cell to become arrested at a specific point in the cell cycle, if previous events have not been completed

Utilize negative signals

What do you think might be the nature of the cell cycle control system?

CYCLIN-CDK COMPLEXES

Cdk (cyclin-dependent kinase): cyclically activated protein kinase

Cyclin: switches Cdk on and off

Figure 18-5 Essential Cell Biology (© Garland Science 2010)

CYCLIN-CDK ACTIVITY AND CELL CYCLE

FOUR CLASSES OF CYCLINS

G1 cyclins promote the cell through “Start” or restriction point in late G1

G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication

S-cyclins bind Cdks during S phase and are required for initiation of DNA replication

M-cyclins promote the events of mitosis

wikipedia

MAJOR CYCLINS AND CDKS

Cyclin-Cdk complex

Vertbrate Budding yeast

CyclinCyclin CdkCdk CyclinCyclin CdkCdk

G1-Cdk cyclin D Cdk4, 6

Cln3 Cdk1

G1/S-Cdk

cyclin E Cdk2 Cln1, 2 Cdk1

S-Cdk cyclin A Cdk2 Cln5, 6 Cdk1

M-Cdk cyclin B Cdk1 Cln1, 2, 3, 4

Cdk1

Figure 18-10 Essential Cell Biology (© Garland Science 2010)

ACTIVATION OF CDKS

Binding to cyclins Phosphorylation by Cdk-activating kinase

(CAK) near the entrance of the active site

Figure 18-9 Essential Cell Biology (© Garland Science 2010)

INHIBITION OF CDK ACTIVITY

Binding of cyclin-Cdk complexes by Cdk inhibitor proteins (CKI)

Proteolysis of cyclin

Figure 18-12 Essential Cell Biology (© Garland Science 2010)

CELL CYCLE CHECKPOINTS At G1 checkpoint, cell

decides whether to commit to another cell cycle.

At each checkpoint, cell may be arrested if conditions are not favorable.

THE S PHASE

Active S-Cdk

Initiation of DNA replication

Prevention of rereplication

INITIATION OF DNA REPLICATION

REGULATION AT THE ORIGIN OF DNA REPLICATION

S-Cdk allows DNA replication to initiate.

Mcm

Mcm

Export from the nucleus

S-CdkM-Cdk

Ubiquitylation by SCF

S-CdkM-Cdk

PREVENTION OF RE-REPLICATION

THE M PHASE

Chromosome separation

Figure 18-17 Essential Cell Biology (© Garland Science 2010)

ROLES OF M-CDK IN MITOSIS

Induces the assembly of the mitotic spindle

Ensures that replicated chromosomes are attached to the spindle

Triggers chromosome condensation, nuclear envelope breakdown, actin rearrangement, reorganization of Golgi apparatus and ER

PO

SIT

IVE F

EED

BA

CK

LO

OP

Positive feedback loop allows for commitment to a cell cycle event.

Figure 18-18 Essential Cell Biology (© Garland Science 2010)

SPINDLE-ATTACHMENT CHECKPOINT

Ensures that all chromosomes are properly attached to the mitotic spindle before sister-chromatid separation occurs

Unattached kinetochores send out a negative signal that blocks activation of Cdc20-APC complex

Binding of Mad2 to unattached kinetochore, leading to inhibition of Cdc20-APC and securin degradation

Exit from Mitosis

Figure 18-29 Essential Cell Biology (© Garland Science 2010)

CREATION OF G1 PHASE

Destruction of M-cyclin at the end of mitosis leads to:

inactivation of Cdc20-APC

activation of Hct1-APC

activation of Sic1 CKI

decrease in the transcription of M cyclin gene

TRANSITION THROUGH START Extracellular signals cause an accumulation of G1

cyclin (not sensitive to Hct1-APC and Sic1) G1-Cdk stimulates transcription of G1/S cyclin gene G1/S-Cdk stimulates transcription of S-cyclin gene

CONTROL OF S-PHASE INITIATION

CELL GROWTH AND CELL CYCLE PROGRESSION

MONITORING OF CELL CYCLE PROGRESSION

Cln3, the budding yeast G1 cyclin, is synthesized in parallel to cell growth

Cells may inherit a fixed amount of inhibitor that binds Cln3

DNA DAMAGE CHECKPOINTS

Checkpoint in late G1 prevents entry into S phase

Checkpoint in late G2 prevents entry into mitosis

G1 CHECKPOINT

DNA damage leads to the activation of p53, a gene regulatory protein

p53 stimulates expression of many genes including a CKI called p21, which binds G1/S-Cdk and S-Cdk

G2 CHECKPOINT

Damaged DNA sends signals to inactivate Cdc25.

Figure 18-17 Essential Cell Biology (© Garland Science 2010)

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CONTROL OF THE CELL CYCLE

PROGRAMMED CELL DEATH

FUNCTION OF APOPTOSIS

To eliminate damaged cells Is an essential part of development in

multicellular organisms Balances cell division to regulate

tissue/organ size

Necrotic cells Apoptotic cells

CASPASE CASCADE

Caspase is a class of proteases

Contain cysteine at their active site

Cleave at specific aspartic acid residue

EXTRACELLULAR CONTROL OF CELL DIVISION

EXTRACELLULAR SIGNALS Mitogens: stimulates cell division by relieving

intracellular negative control

Growth factors: stimulates cell growth by promoting synthesis of proteins and other macromolecules and inhibiting their degradation

Survival factors: promotes cell survival by suppressing apoptosis

PDGF: PLATELET-DERIVED GROWTH FACTOR

Functions as a mitogen

Secreted by platelet cells to stimulate cell division during wound healing

Can act on multiple cell types: fibroblasts, neuroglial cells, smooth muscle cells

MITOGEN SIGNALING PATHWAY(THROUGH GTPASE RAS AND MAP KINASES)

OVERACTIVE MITOGENIC SIGNAL RESULTS IN CELL CYCLE ARREST OR APOPTOSIS

REPLICATIVE CELL SENESCENCEFibroblasts from normal human

tissues can only go through 25-50 population doubling when cultured in standard mitogenic medium

GROWTH FACTOR SIGNALING PATHWAY

PI 3-kinase phosphorylates inositol phospholipid in the membrane activating S6 kinase which activates components of translational machinery

NERVE CELLS GROWTH AND APOPTOSIS

Survial factors are produced in limited amount

Nerve growth factor (NGF)

SURVIVAL FACTOR SIGNALING PATHWAY

ANCHORAGE-DEPENDENT CELL DIVISION

Cells are growth over non-adhesive substratum with or without a patch of adhesive palladium, fed with 3H-thymidine and autoradiographed.

Integrins (cell surface matrix receptors) interact with laminin and/or fibronectin (extracellular matrix molecules, leading to activation of FAK (focal adhesion kinase) and signaling pathways that promote cell survival, growth and division

Actin is labeled in green and proteins with phosphotyrosines are labeled in red

EXTRACELLULAR NEGATIVE SIGNAL PROTEINS TGF- signal proteins inhibit the proliferation

of many cell types (blocking progression through G1 or stimulating apoptosis)

BMP (bone morphogenetic protein) triggers apoptosis of cells between developing digits of a mouse paw

EXTRACELLULAR NEGATIVE SIGNAL PROTEINS Myostatin inhibits proliferation of myoblasts

that fuse to form muscle cells Mutations in myostatin gene can cause an

increase in muscle cell size and number

CONTROL OF BODY SIZE

Through the control of total cell mass

Salamanders of different ploidy levels are of the same body size

But their cell size and cell number are differentKidney tubules

hindbrain

Haploid

Tetraploid

QUESTION

Describe a mechanism by which Cdk is activated during the cell cycle.