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•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
05-05-16 Lecture 11
•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
05-05-16 Lecture 11
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
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