•Cell division results in two identical cells

•During cell division – the ability to organize DNA in time and space (location in the cell) is critical!

•The mitotic phase of the Cell Cycle alternates with a interphase

•Cell cycle is controlled by a molecular control system

Key Concepts

Cell Cycle - Introduction05-05-16 Lecture 11

Key Questions that scientist want to understand:

Cell Cycle - Introduction

•Total genetic material is called the GENOME

Prokaryotic Eukaryotic (human cells)

•Chromosomes 1 circular, + plasmids several linear

•DNA 4.6 million base pairs (BP) 3 Billion BP (human)

•Cell division time 20 minutes 24 hours

•Mechanism of division binary fission mitosis, cytokinesis

• Cell Division

• Duplicate of DNA with high fidelity• Distribute DNA evenly to the 2 progeny

(WITHOUT MISTAKES!!!)(Order of genes stays the same)

05-05-16 Lecture 11

Cell Cycle - Introduction

Somatic Cells – all cells except for reproductive cells200 Trillion cells in your body made by Mitosis and Cytokinesis!

Reproductive cells (gametes) – sperm and egg cellsMeiosis – variation of cell division that makes non-identical daughter cells

05-05-16 Lecture 11

Interesting facts• 25,000,000 cells divide per minute in our bodies• Every 8 seconds DNA suffers a break at least once!• Some cells continuously divide (skin)• Some cell types are quiescent, unless provoked (blood)• Some cells never divide (muscle, neurons)• Some cells are dead but still part of our body (hair, nails)• Division leads to death, eventually !• Control of cell division is control of cancer.

Stages of the Cell Cycle

M G1

SG2

G1= Gap phase #1 : wait, grow

S = synthesis of DNA

G2= Gap phase #2 : checkpoints•check to see if DNA is replicated – fidelity•Prepare cytoskelton for cytokinesis

M = Mitosis : divide the DNA andcytokinesis

6h

12h

30min.

5-6h

05-05-16 Lecture 11

Anatomy of a EukaryoticMitotic Chromosome

•DNA is bound by proteins: CHROMTIN

•Major type of protein is called HISTONES•DNA is efficiently packed by wrapping around histones.

•In Mitosis : called SUPERCOILING

05-05-16 Lecture 11

Anatomy of a EukaryoticMitotic Chromosome

0.5 µm

Figure 12.4

Sister chromatids(identical)

Sister chromatids

Chromatid = 1 Chromosome

TelomeresEnds of DNA Centromere

where sister chromatids attach

05-05-16 Lecture 11

Cell Cycle – Dividing the DNA EVENLY between 2 cells

1. S-phase Duplicate DNA

S

2. Attach to SPINDLE; microtubules hook on to centromere via KINETOCHORE (made of proteins)

3. Pull Chromatids apart (separate) using microtubule motors : Kinesins

4. Reform into 2 cells around DNA

05-05-16 Lecture 11

•Interphase•G1 : receive a signal to divide•S : duplicate DNA•G2: CENTRIOLES duplicated

•MITOSIS

•PROHASE DNA dondensedCentrioles seapated to opposite sides of nucleusStart spindle formation

•PROMETAPHASE Nuclear enevelope fragmentsMTs can now bind at kinetochorecentrioles are now at opposites sides

•METAPHASE Chromosomes lined up at middle of spindlecalled “METAPHASE PLATE”

•ANAPHSE 2 sister chromatids are separated – pulled apart to opposite spindle poles

Cell Cycle – MITOSIS05-05-16 Lecture 11

•ANAPHSE 2 sister chromatids are separated – pulled apart to opposite spindle poles

•TELOPHASE chromatids well separatedspindle pole disassemblesnuclear envelope reforms around DNA

CYTOKINESIS Cleavage furrow forms- involves actin and myosin: contraction

Cell Cycle – MITOSIS05-05-16 Lecture 11

G2 OF INTERPHASE PROPHASE PROMETAPHASE

Centriole Duplicated

Chromasomes(duplicated)

Early mitoticspindle

CentromereFragmentsof nuclearenvelope

Kinetochore

Nuclearenvelope

Plasmamembrane

Sister chromatidsmicrotubule attaches

to KinetochoreFigure 12.6

Cell Cycle – MITOSIS05-05-16 Lecture 11

Spindle poleDaughter chromosomes

METAPHASE ANAPHASE

TELOPHASE AND CYTOKINESIS

Metaphaseplate Nucleolus

forming

Cleavagefurrow

Nuclear envelopereforming

Figure 12.6

Cell Cycle – MITOSIS05-05-16 Lecture 11

05-05-16 Lecture 11

Cell Cycle – Checkpoints

•“STOP” and “GO-ahead” signals

•G1 checkpoint “restriction point”•Wait for a growth factor signal?•Sufficient energy?•Sufficient space•Internal timing of control system?

•After S-phase (replicated DNA) - G2 checkpoint•Quality control: look for gaps in DNA – i.e. is replication finished??????

•Are microtubules, centrioles, cytoskeleton, and organelles ready????

•M checkpoint •Is DNA divided evenly?????

05-05-16 Lecture 11

Cell Cycle – Checkpoints

•“STOP” and “GO-ahead” signals

Figure 12.14

Control system

G2 checkpointM checkpoint

G1 checkpoint

G1

S

G2M

05-05-16 Lecture 11

Cell Cycle – Checkpoints

•“STOP” and “GO-ahead” signals

•Most cells are actually waiting in G0 – until the right signal comes along

•Some cells stay in G0 (e.g. neurons)

G1 checkpoint

G1G1

G0

Figure 12.15

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•What controls the progression of the cell cycle?

•Molecular control System- that involves Checkpoints

•

Cell Cycle – Control System05-05-16 Lecture 11

Experiment 1 Experiment 2

S MG1 G1

Cells at different stages of cell cycle

were fused together

S MS M

G1 cell initiated DNA replication

– S phase

G1 cell initiated Mitosis without replicating its

DNA

Cell Cycle – Evidence for a Control System05-05-16 Lecture 11

Cell Cycle – the M-phase promoting Factor(MPF) - part of the control system

•M-phase promoting Factor (MPF)

•Cyclins

•Cyclin-dependent kinases (CDKs)

• allosteric regulators of CDKs•Expressed cyclically

• kinase that is only active when bound to cyclin activator

G1G1 S G2 G2SM M

MPF activity

Cyclin

Time

MK

inas

e

acti

vity

05-05-16 Lecture 11

Cell Cycle and Cancer

•Cells that have lost there control over cell division!

•~85% of cancer cells have a mutation in the DNA•Lose a checkpoint control

•15% - caused by virus: which induces S phase

•Benign tumor•Cell still looks the same•But has uncontrolled growth: Tumor•Damages neighboring cells (tissues)

•Malignant tumor•Cell becomes undifferentiated•Uncontrolled growth•Loses its attachment to neighbors•Metastasis – can spread thru the body

Normal cell will stop dividing when they are crowded - Contact Inhibition!(Negative feedback mechanism)

05-05-16 Lecture 11

Hallmarks of Cancer: 6 changes that happen to cancer cells

•Self-sufficiency in growth signals •Cells produce their own growth signals

•Insensitivity to negative growth signals•While normal cells respond to “stop growth” signals – cancer cells do not

•Evasion of apoptosis (programmed cell death)•Surrounding cells begin to die

•Acquisition of limitless proliferative capacity•Uncontrolled cell growth

•Sustained Angiogenesis (blood supply)•Cancer cells create their own blood supply by recruiting new blood vessels

•Tissue invasion and metastasis•Move to other tissues and create new tumors

More about Cell Cycle and Cancer05-05-16 Lecture 11

A TYPICAL FAMILY TREE OF INHERITED CANCER SYNDROME

IndividualsWith Related Cancer

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Inherited Cancer Syndrome:

Germline mutation

Early onset

More than one tumor

Rare

Sporadic Cancer:

Somatic mutation

Later in life

Clonal tumor

One in four people

Inherited vs. Sporadic Cancer05-05-16 Lecture 11

Accumulation of genetic alterations and the progression of Cancer

05-05-16 Lecture 11