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A cancer is an uncontrolled proliferation of cells
Failure in the mechanisms by which the cell cycle isregulated can lead to uncontrolled cell growth and thedevelopment of cancer
In some the rate is fast; in others, slow; but in allcancers the cells never stop dividing.
Cancer cells are usually less differentiated than thenormal cells of the tissue where they arose.
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Cell Cycle
The repeating sequence of growth anddivision through which cells pass eachgeneration
The purpose of the cell cycle is to allowcells to reproduce without alteration ofgenetic material
The stages are well preserved betweenspecies
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Why do cells devide?
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Events of cell cycle
G1 =Growth andpreparation of thechromosomes forreplication
S = Synthesis of DNA
G2 = Preparation formitosis
M = Mitosis
Periode between M and S iscalled G1;
between S and M is G2
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Higly regulated process controlled by a large numberof factors include:
Growth stimulating factors
Growth inhibiting factors
Enzymes that alter functional state of other proteinsby adding (kinases) or removing (phosphatases)phosphate groups
Failure in the mechanisms by which the cell cycle is
regulated can lead to uncontrolled cell growth and thedevelopment of cancer
Cell cycle progression
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There are several factors that regulate thecell cycle and assure a cell divides correctly
There are several factors that regulate thecell cycle and assure a cell divides correctly
Control of Cell Cycle
There are several factors that regulate the cellcycle and assure a cell divides correctly
1. Before a cell divides, theDNA is checked to makesure it has replicated
correctly. (If DNA doesnot copy itself correctly, agene mutation occurs.
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There are several factors that regulate thecell cycle and assure a cell divides correctly
There are several factors that regulate thecell cycle and assure a cell divides correctly
Control of Cell Cycle
There are several factors that regulate thecell cycle and assure a cell divides correctly
2. Chemical Signals tell acell when to start and
stop dividing
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Control of Cell Cycle
There are important checkpoints during the cell cycle: At the G1 S transition
At the S G2 transition
At the G2 M transition
Regulation of the cell cycle occurs as a consequenceof cyclin Cdk interaction
Other proteins such as P53, Rb and oncogene play a
role in regulating the cell cycle
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Cyclins and Cyclin Dependent Kinases(Cdk)
Cyclin Cdk Process regulated
Cyclin DCyclin ECyclin ACyclin ACyclin B
Cdk 4,6Cdk 2Cdk 2Cdk 1(Cdc2)Cdk 1
G1 phase progressionG1 to S phaseS phase progressionS through G2M phase
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Waves of Cyclin-Cdk Activity ControlThe Cell Cycle
G1 S G1G2 M
Cyclin D-Cdk 4/6
Cyclin E-Cdk 2CyclinA-Cdk1
Cyclin B-Cdk1
GF
Kin
aseActivit
y
Time
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The cell cycle control system hascheckpoints during G1, G2, S and M
Checkpoint signals report cells status:
Is the cell big enough?
Is environment favorable?
Is DNA replicated?
Are chromosomes attached to oppositepoles?
Checkpoints
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G1 G2S prophase metaphase anaphase Cytokinesis
Mitosis
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Labile Epithelial, Lymphoid,Haemopoietic
Stable Liver, Pancreas, Salivary
gland,Endocrine organs
Permanent Neurons, Skeletal muscle,
Cardiac muscle
Regenerative Capacity
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It was originally assumed that cancerarose from a population of cells thatproliferated more rapidly than normal cells
It is now known that many malignant cellshave longer cell cycle times than theirnormal counterparts
Cell proliferation and cancer
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Malignancies probably arise when there isan imbalance between cell production andcell loss
Cell loss occurred through necrosis,apoptosis and surface shedding
Abnormalities of the cell cycle do not
explain all of the growth of malignanttumors and they are clearly not importantin invasion and metastasis
What happens in malignancy?
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Cell Cycle Is Regulated byOpposing Effects of Positive and NegativeFactors
S
G2 G1
M
Cyclin
Cdk
+
P53
Rb
-
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Cell Cycle Is Regulated ByOpposing Effects of Positive and Negative
Factors
Tumor Suppressor(P53, Rb)
Oncogene(BCl2,BRCA1)
Tumor Suppressor
(P53, Rb)
Oncogene
(BCl2,BRCA1)
Cell proliferation
Cell proliferation
Cell death
Cell death
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APOPTOSIS
For every cell, there is time to live and atime to die
There are two ways in which cells die: They are killed by injuries agents
They are induced to commit suicide (apoptosisor Programmed cell death;PCD)
Two forms of cell death Necrosis
Apoptosis
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Death by Injury
Cells that are damaged by injury, such asby:
Mechanical damage Exposure to toxic chemicals
Undergo a characteristic series of changes:
They are swell
The cell contents leak out, leading to;
Inflammation of surrounding tissues
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Death by Suicide (Apoptosis)
Cells that are induced to commit suicide:
Shrink
Have their mitochondrial break down
Develop bubble-like blebs on their surface
Have the chromatin in their nucleusdegraded and show chromatin
condensation
Break into small, membrane-wrapped,fragment
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Apoptosis Versus Necrosis
Apoptosis
Central part of normal
development Genetically mediated
Involve inorganogenesis, tissuehomeostasis
Necrosis
Results from cell
metabolic collapse Response to injury or
toxic damage
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Apoptosis Versus Necrosis
Apoptosis Shrinkage of cell
Little or no swellingof mitochondria
Intact membrane
Degradation of DNAinto multiple of 180bp
Little or noinflammatoryresponse
Necrosis Swelling of cell
Swelling ofmitochondria
Loss of membraneintegrity
Random degradationof DNA
Intense inflammatoryresponse
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Why Should a Cell CommitSuicide?
There are two different reasons
Apoptosis is needed for proper development The formation of the fingers and the toes of the
fetus requires the removal, by apoptosis of thetissue between them
Apoptosis is needed to destroy cells thatrepresent a thread to integrity of the organism
Cells infected with viruses Cells of the immune system
Cells with DNA damage
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What Makes Cell Decide toCommit Suicide?
The balance between:
The withdrawal of positive signals; that
is, signal needed for continued survival(GF, cytokines, oncogenes)
The receipt of negative signals
(increased levels of oxidant damage ofDNA, tumor suppressor)
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