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Chapter 17. The Cell Cycle and Programmed Cell Death Overview Molecular Parts list Intracellular Control Mechanisms Apoptosis Extracellular Control. Overview of the Cell cycle. Metaphase Details - Classical Stages from Microscopy. Interphase: 3 generic sub-phases. G1 - gap1 or growth

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Chapter 17

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Chapter 17 l.jpg

Chapter 17

  • The Cell Cycle and Programmed Cell Death

    • Overview

    • Molecular Parts list

    • Intracellular Control Mechanisms

    • Apoptosis

    • Extracellular Control


Overview of the cell cycle l.jpg

Overview of the Cell cycle


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Metaphase Details - Classical Stages from Microscopy


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Interphase:3 generic sub-phases

G1 - gap1 or growth

S - synthesis

G2 - gap 2


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Alternative cell cycles and cytokinesis strategies in 2 yeast species


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Genetic analysis of cell cycle control with temperature sensitive cdc mutants in yeast

Ts cell-division-cycle (cdc) mutants are conditional,

growth inhibited at high temp only

Cdc mutants distinguished from others by microscopy. How?

Cdc mutants can be organized into complementation groups. How?


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S. cerevisiae cdc15 cell cycle arrest

A - wild type -non-synchronized cells

B - cdc15 cells grown at the restrictive temperature


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Huge Xenopus oocytes for cell cycle biochemistry

Fertilized eggs undergo synchronous cell division without transcription

Oocytes or eggs can be injected with proteins, RNA, inhibitors etc.


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Cell-free oocyte cytoplasm can “cycle “ in a test tube

Fractionation of an active extract can lead to identification of cell cycle components


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Identifying cell-cycle phases in cell populations

Recent DNA synthesis can be detected by pulse labeling

Brief exposure to 3H thymidine or Br-dUTP can identify cells active in DNA replication

Flow cytometry can characterize (and separate) cells based on DNA content


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The Laundromat model of the cell cycle

Desirable control features

Unidirectionality

Feedback to make sure that necessary prior processes are complete

Error recognition - in case things don’t work normally

External controls to modify the cycle for different cell types/situations


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Generic cell cycle checkpoints


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Cyclins and cyclin dependent kinases (Cdk’s) control the cell cycle

Cyclins - regulatory subunits

Synthesized and degraded cyclically

Cdks - catalytic subunits

Kinase (phosphotransferase) activity is dependent on cyclins

Cdk levels remain relatively constant


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Fictitious “Core” cyclin Cdk control cycle

S cyclin synthesized during G1

Activates Cdk for phosphorylation of S-phase targets (DNA replication)

S-cyclin degradation system also activated

M cyclin synthesized during G2

Activates Cdk for phosphorylation of M-phase targets (segregation)

M-cyclin degradation system also activated


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G1/S cyclins commit the cell to a new round of replication

S cyclins trigger initiation of replication

M cyclins promote mitosis

G1 cyclins (optional) initiate a new cell

Multiple cyclins and Cdks are widely conserved


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Structural basis of Cdk Activation


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Other modulators of Cyclin/Cdk Activity

Some kinases inhibit Cyclin/Cdk activity

Wee1 (small cell mutant) inhibits by phosphorylation

Cdc25 phosphatase reverses the effect

Cdk inhibitory protens (CKIs) inhibit by direct binding


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Regulated Proteolysis

Anaphase promoting complex (APC) targets M-cyclin

SCF targets CKI


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Ubiquitinylation can target proteins for destruction


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Intracellular Control Mechanisms

S phase Cyclin/Cdk complexes issue DNA replication licenses

M phase Cyclin/Cdk complexes trigger entry into mitosis

DNA replication checkpoint

Chromosome separation

potentiated by M-cdk

Triggered by proteolysis (APC)

Spindle-attachement checkpoint

M-Cdk inactivation required for exit from mitosis

Cdks are inactived by CKIs in G1


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Cell fusion experiments can detect positive and negative regulatory components


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S-Phase Cyclin–Cdk Complexes (S-Cdks) Initiate DNA Replication Once Per Cycle

Unphosphorylated ORC binds to origins

Cdc6 binds to ORC in G1

Mcm (mini chromosome maintenance) proteins assemble to complete the Pre replication complex (PreRC)

S-Cdk phosphorylates Cdc6 and subsequently ORC and Mcm

ORC remains phosphorylated until the end of the cell cycle

After replication Mcm is exported from the nucleus


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Origin recognition complexes are phosphorylated by S-Cdks


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The Activation of M-Phase Cyclin–Cdk Complexes (M-Cdks) Triggers Entry into Mitosis

M-cyclin levels rise in G2

M-Cdk is held in check by phosphorylation until Cdc25 phosphatase produces a small amount of active M-Cdk

M-Cdk activates Cdc25, inactivatesWee1 and thus promotes a burst of Active M-Cdk


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Activation of M-Cdk to begin mitosis


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The DNA replication checkpoint

Hydroxyurea blocks replication

Caffeine prevents proper checkpoint signaling


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Proteolysis

APC destroys securin releasing separase

Separase destroys cohesin and allows chromosome separation that begins anaphase

Degradation of M-Cyclin is required for completion of anaphase


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APC


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Exit from Mitosis Requires the Inactivation of M-Cdk


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Sphase initiation


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Nutritional control


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DNA damage sensed by P53


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Cell cycle overview


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Apoptosis

Programmed cell death is a normal cellular function used in

Development to remove excess cells

Adulthood to maintain the proper cell numbers

Disease to remove damaged cells

Caspases are proteases that cleave each other and cellular components to disassemble cells

Caspase activity can be triggered by internal or external signals


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Sculpting in Development


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Necrosis vs Apoptosis

Injured Cells (A) can undergo Necrosis spilling their contents and triggering inflammatory responses

Appoptosis (B & C) results in the orderly destruction of the cell and packaging into membrane bound vesicles


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Caspases trigger apoptosis by a cascade of proteolyis


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Extracellular Activation of Apoptosis


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Intracellular Activation of Apoptosis


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Mitochondrial permeability is controlled by Bcl-2 family proteins

Bcl-2 family proteins assemble into homo and hetero oligomers

Bcl-2 and Bcl-Xl block cytochrome C release from mitochondria and inhibit apoptosis

Bad, Bax and Bak promote apoptosis

IAP (inhibitors of apoptosis) inhibit caspases, synthesized by viruses to delay apoptosis until after viral replication is complete


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Extracellular control of cell size, cell division and cell death

Regulated by extracellular signals

Mitogens - stimulate cell division

Growth factors - stimulate cell growth

Survival Factors - inhibit apoptosis

Signals are transduced through Cell surface receptors


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Platelet Derived Growth Factor

PDGF is released by platelets in at the site of a wound (triggered by a protease cascade of clotting factors)

Blood Serum (cleared by clotting) but not plasma (cleared by centrifugation before clotting) supports growth of epidermal cells


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Mitogen Signal Transduction Pathway


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Overactivity of cell cycle stimulators normally triggers arrest and apoptosis


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Normal somatic cells have limited growth potential

Progressive increases in Cdk inhibitors (CKIs)

Progressive shortening of telomeres in cells that do not express telomerase

Telomeres shortened with each replication cycle

Non-telomere sequences exposed at chromosome ends are recognized asDNA damage


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Growth Factors

A signal transduction through phosphatidyl inositol pathway

Kinase cascade leads to increased translation

Some factors stimulate both growth and cell cycle progression


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Nerve growth factors can influence both rate and direction of growth


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Neural pathfinding depends on cell growth and apoptosis

Cell growth initially responds to gradients of growth factors.

Not all nerve cells reach their target

Neurons that do not make it (or make it late) die


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Death by neglect: continuous stimulation required to prevent Apoptosis


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Normal cells need both mitogens and “anchorage”- to enter a new cell cycle


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Signals from the substratum


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Myostatin Mutants decrease apoptosis in muscle tissue


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BCR and ABL


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Leukaemogenic signalling of BCR-ABL.


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The development of chronic myelogenous leukaemia.


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