2006-2007AP Biology

Regulation of Cell Division

AP Biology

Coordination of cell divisionA multicellular organism needs to coordinate cell division across different tissues & organs

critical for normal growth,development & maintenance

coordinate timing ofcell divisioncoordinate rates ofcell divisionnot all cells can have the same cell cycle

AP Biology

G2

S G1

Mmetaphase

prophaseanaphase

telophase

interphase (G1 , S, G2 phases)mitosis (M)cytokinesis (C)

C

Frequency of cell division varies by cell typeembryo

cell cycle < 20 minuteskin cells

divide frequently throughout life12-24 hours cycle

liver cellsretain ability to divide, but keep it in reservedivide once every year or two

mature nerve cells & muscle cellsdo not divide at all after maturitypermanently in G0

Frequency of cell division

AP Biology

Overview of Cell Cycle ControlTwo irreversible points in cell cycle

replication of genetic materialseparation of sister chromatids

Checkpointsprocess is assessed & possibly halted

centromere

sister chromatids

single-strandedchromosomes double-stranded

chromosomes

There’s no

turning back,

now!

AP Biology

Checkpoint control systemCheckpoints

cell cycle controlled by STOP & GOchemical signals at critical pointssignals indicate if key cellular processes have been completed correctly

AP Biology

Checkpoint control system3 major checkpoints:

G1/Scan DNA synthesis begin?

G2/Mhas DNA synthesis been completed correctly?commitment to mitosis

spindle checkpointare all chromosomes attached to spindle?can sister chromatids separate correctly?

AP Biology

G1 /S checkpointG1/S checkpoint is most critical

primary decision point“restriction point”

if cell receives “GO” signal, it dividesinternal signals: cell growth (size), cell nutritionexternal signals: “growth factors”

if cell does not receivesignal, it exits cycle & switches to G0 phase

non-dividing, working state

AP Biology

G0 phase

MMitosis

G1Gap 1

G0Resting

G2Gap 2

SSynthesis

G0 phasenon-dividing, differentiated statemost human cells in G0 phase

liver cellsin G0, but can be “called back” to cell cycle by external cues

nerve & muscle cellshighly specializedarrested in G0 & can never divide

AP Biology

How do cells know when to divide?cell communication signals

chemical signals in cytoplasm give cuesignals usually mean proteins

activatorsinhibitors

Activation of cell division

experimental evidence: Can you explain this?

AP Biology

“Go-ahead” signalsProtein signals that promote cell growth & division

internal signals“promoting factors”

external signals“growth factors”

Primary mechanism of controlphosphorylation

kinase enzymeseither activates or inactivates cell signals

AP Biology

Cell cycle signals Cell cycle controls

cyclinsregulatory proteinslevels cycle in the cell

Cdk’scyclin-dependent kinasesphosphorylates cellular proteins

activates or inactivates proteinsCdk-cyclin complex

triggers passage through different stages of cell cycle

activated Cdk

inactivated Cdk

AP Biology

Cyclins & CdksInteraction of Cdk’s & different cyclins triggers the stages of the cell cycle

Leland H. Hartwellcheckpoints

Tim HuntCdks

Sir Paul Nursecyclins

1970s-’80s | 2001

AP Biology

Cdk / G1cyclin

Cdk / G2cyclin (MPF)

G2

S

G1

CM

G2 / M checkpoint

G1 / S checkpoint

APC

Active Inactive

ActiveInactive

InactiveActive

mitosis

cytokinesis

MPF = Mitosis Promoting FactorAPC = Anaphase Promoting Complex

• Replication completed• DNA integrity

Chromosomes attached at metaphase plate

Spindle checkpoint

• Growth factors• Nutritional state of cell• Size of cell

AP Biology

Cyclin & Cyclin-dependent kinasesCDKs & cyclin drive cell fromone phase to next in cell cycle

proper regulation of cell cycle is so key to life that the genes for these regulatory proteinshave been highly conserved throughevolutionthe genes are basically the same in yeast, insects, plants & animals (including humans)

AP Biology

External signalsGrowth factors

coordination between cellsprotein signals released by body cells that stimulate other cells to divide

density-dependent inhibitioncrowded cells stop dividingeach cell binds a bit of growth factor

not enough activator left to trigger division in any one cell

anchorage dependenceto divide cells must be attached to a substrate

“touch sensor” receptors

AP Biology

E2F

nucleuscytoplasm

cell division

nuclear membrane

growth factor

protein kinasecascade

nuclear pore

chromosome

Cdkcell surfacereceptor

P

PP

P

P

E2FRb

Rb

Growth factor signals

AP Biology

Example of a Growth FactorPlatelet Derived Growth Factor (PDGF)

made by platelets in blood clotsbinding of PDGF to cell receptors stimulates cell division in fibroblast (connective tissue)

heal wounds

Don’t forgetto mention

erythropoietin

!(EPO)

AP Biology

Growth Factors and CancerGrowth factors can create cancers

proto-oncogenesnormal growth factor genes that become oncogenes (cancer-causing) when mutatedstimulates cell growthif switched “ON” can cause cancerexample: RAS (activates cyclins)

tumor-suppressor genesinhibits cell divisionif switched “OFF” can cause cancerexample: p53

AP Biology

Cancer & Cell GrowthCancer is essentially a failureof cell division control

unrestrained, uncontrolled cell growthWhat control is lost?

lose checkpoint stopsgene p53 plays a key role in G1/S restriction point

p53 protein halts cell division if it detects damaged DNAoptions:

stimulates repair enzymes to fix DNAforces cell into G0 resting stagekeeps cell in G1 arrestcauses apoptosis of damaged cell

ALL cancers have to shut down p53 activity

p53 discovered at Stony Brook by Dr. Arnold Levine

p53 is the

Cell Cycle

Enforcer

AP Biology

DNA damage is causedby heat, radiation, or chemicals.

p53 allows cellswith repairedDNA to divide.

Step 1

DNA damage iscaused by heat,radiation, or chemicals.

Step 1 Step 2

Damaged cells continue to divide.If other damage accumulates, thecell can turn cancerous.

Step 3p53 triggers the destruction of cells damaged beyond repair.

ABNORMAL p53

NORMAL p53

abnormalp53 protein

cancercell

Step 3The p53 protein fails to stopcell division and repair DNA.Cell divides without repair todamaged DNA.

Cell division stops, and p53 triggers enzymes to repair damaged region.

Step 2

DNA repair enzymep53protein p53

protein

p53 — master regulator gene

AP Biology

Development of CancerCancer develops only after a cell experiences ~6 key mutations (“hits”)

unlimited growthturn on growth promoter genes

ignore checkpointsturn off tumor suppressor genes (p53)

escape apoptosisturn off suicide genes

immortality = unlimited divisionsturn on chromosome maintenance genes

promotes blood vessel growthturn on blood vessel growth genes

overcome anchor & density dependenceturn off touch-sensor gene

It’s like an

out of control

car!

AP Biology

What causes these “hits”? Mutations in cells can be triggered by

UV radiationchemical exposureradiation exposureheat

cigarette smokepollutionagegenetics

AP Biology

TumorsMass of abnormal cells

Benign tumor abnormal cells remain at original site as a lump

p53 has halted cell divisionsmost do not cause serious problems &can be removed by surgery

Malignant tumorscells leave original site

lose attachment to nearby cellscarried by blood & lymph system to other tissuesstart more tumors = metastasis

impair functions of organs throughout body

AP Biology

Traditional treatments for cancersTreatments target rapidly dividing cells

high-energy radiationkills rapidly dividing cells

chemotherapystop DNA replicationstop mitosis & cytokinesisstop blood vessel growth

AP Biology

New “miracle drugs”Drugs targeting proteins (enzymes) found only in cancer cells

Gleevectreatment for adult leukemia (CML)& stomach cancer (GIST)1st successful drug targeting only cancer cells

Novartes

without Gleevec

with Gleevec

2006-2007AP Biology

Any Questions??