Cell Biology: The Cell Division Cylce

Essential Cell Biology
Third Edition
Chapter 18 The Cell Division Cycle
Copyright Garland Science 2010
Cell Cycle Cell duplicates its contents and then divides in two Essential mechanism by which ALL living things reproduce Bacteria and yeast - each cell division produces new organism Many rounds cell division required for multicellular organisms
Sarah E Golding PhD.
Compact Mitotic Chromosome
During S-phase the chromosomes are copied
Each Early M-phase chromosome has two sister chromatid (exact copies)
The chromatids are joined together at the centromere
One copy of a chromosome formed by DNA replication that is still joined at the centromere to the other copy
Figure 5-17 Essential Cell Biology ( Garland Science 2010)
Telomeres form caps at the ends of each chromatid
Steps of Cell Division

Eukaryotic Cell Cycle Divided into Four Interphase: All thePhases: rest! G1, S and G2 = Interphase
4.
3. 2.
Eukaryotic Cell Cycle Divided Four Phases: M-Phase: Cell into divisionMitosis

Cell-cycle control system

Events of cell cycle occur in proper order and that each has been completed before advancing to the next
Must have DNA Replication before Mitosis
Critical checkpoints = molecular brakes

Ensure each phase is completed properly before starting next phase
Cell cycle check points
Intra S
The DNA damaged so badly that replication needs to be slowed for repair?
Nutrients and growth factors?
Cyclin-dependent Protein Kinases- Cdks

Cdks - kinases of the cell cycle control system
Activated at appropriate times in cell cycle & then are quickly deactivated
Cyclins - no enzymatic activity but have to bind to Cdks to make them enzymatically active
***Cyclin-Cdk complexes
Trigger entry into S phase or M phase Cell cycle control mechanisms are highly conserved through evolution
Cdks bind cyclins

Cdks must bind to the regulatory cyclin proteins to become active Once active the Cdk/Cyclin complex phosphorylates proteins required to drive the cell cycle forward This process acts as molecular checks and balances ensuring all is ready before the cell proceeds
Changes in cellular concentrations of cyclins controls the cell cycle (controlled by translation and protein degradation)

Kinases drive the cell cycle
During interphase the cell makes cyclins When the cell needs to transition to mitosis Cdks activate cyclin activity Changes in cellular concentrations of cyclins controls the cell cycle (controlled by translation and protein degradation)
Phosphorylation controls cyclin-CdK activity
For a Cdk to be active it must be phosphorylated at one site to become primed for action Think starting the engine of the car While the cell is preparing 2 INHIBITORY phosphates are also places on the complex Think putting the parking break on while you adjust your mirror, put on seat belt, put into gear At the correct moment the inhibitory phosphates are quickly removed by a phosphatase and the cyclin-Cdk complex is active The parking break comes off and the car moves forward
Different cyclins control different cell cycle phases
These complexes are formed in response to extra-cellular signals that tell the cell its time to divide Different cell types divide in response to different stimuli! What if we could stimulate neurons to divide? You need to know these!
Table 18-2 Essential Cell Biology ( Garland Science 2010)
Different cyclins control different cell cycle phases

Cyclin proteins are degraded by proteolysis to help regulate the timing of the cell cycle
Remember: Ubiquitination is the cellular signal to degrade a protein

The resting phase
G0 Phase
Not all cells are actively growing and dividing all the time Liver cells divide every year or so Gut cells divide once every 12 hrs -----
Withdraw TEMPORARILY Actively growing Terminal Differentiated State
Some cells never divide, such as neurons --(might not be as true as we first thought!) What if we could stimulate this?
G0 also referred to as quiescence
Transition out of G0 requires accumulation of G1 cyclins (induced by signals from the environment)
S-phase
S-phase
Synthesis - DNA Replication
DNA Replication begins where??????
S-Cdk involved in initiating DNA replication!

Origin Recognition Complex (ORC) - remains bound to origins or replication throughout the cell cycle - serves as a landing pad for regulatory proteins that bind before the S phase Cdc6 - regulatory protein. Concentration increases in early G1 binding of Cdc6 promotes binding of additional proteins to form a pre-replicative complex
How is S-phase initiated?

S-Cdk triggers S-phase by facilitating the activation of the replication machine Cdc6 helping assemble the machinary
S-Cdk also stops rereplication at the same origin by inducing the degradation of cdc6 You need to know this!
Cohesins tie together the replicated chromosome

Hold together sister chromatids Vital to correct division of the chromosomes
** Assemble along the length as DNA is replicated Cleaved in late mitosis What would happen if cohesin rings were defective?
ERRORS in chromosome segregation

M-phase
http://www.youtube.com/watch?v=ZEwddr9ho-4
M-phase is triggered by M-Cdk

M-Cdk triggers the condensation of the chromosomes (tightens the chromatin) Similar regulation to S-Cdk, receives an activating phosphate and an inhibitory phosphate keeping the complex INACTIVE (again starting engine but with parking break on!) Complex activity is induced by the phosphatase Cdc25 removing a phosphate
You need to know this!

M-Cdk positively feeds back to further increase mitotic signals
Active M-Cdk can positively feed back on itself by activating additional cdc25 to AMPLIFY the mitotic response Cdc25 activity can be influenced by signals from the environment via MAPK cascades to increase or decrease mitotic events!

Condensins help condense chromatin
M-Cdk triggers the assembly of condensin complexes onto DNA phosphorylating some of the condensin subunits Condensins assemble on each individual chromatid at the start of M phase - coil up the DNA to help chromatids condense
You should have this memorized
Form metaphase plate
Two transient cytoskeletal structures mediate M-phase in animal cells
mitosis
cytokinesis

Chromosomal segregation is facilitated by the cytoskeleton
3 different types of Microtubules are involved

Cohesion rings are cleaved allowing sister chromatids to separate to the opposite poles of the cell

The centrosome cycle

REMEMBER? Centrosome is the major micro-tubule organizing center It must be duplicated to allow each cell to receive a centrosome
Forms the two poles of the cell

As the 2 centrosomes separate they produce an array of microtubles the aster

Mitotic spindle assembly

REMEMBER? Microtubules continuously growing and shrinking Dynamic Instability During M-phase microtubules are very actively growing/shrinking from both centrosome forming spindle poles
At some point microtubules interact with tubules from the opposite centrosome and stabilize
This forms interpolar microtubules Interpolar microtubules assembly is driven by large motor proteins that crosslink and stabilize
Prometaphase nuclear membrane degrades and Kinetochores attach chromosomes to the mitotic spindle
Prometaphase begins with the breakdown of nuclear pores and the nuclear lamina The spindle microtubles are already being formed As the nuclear membrane breaks down the spindle gain access to the chromosomes and capture them
Spindle bind via Kinetochores at the centromeres (one on each chromatid)

Metaphase chromosomes line up halfway between poles
Anaphase - Sister chromatids separate
Chromosomes lines up halfway between the spindle during metaphase Chromosomes then oscillate back and forth in a tug of war towards the opposite spindles
Chromosome separation is triggered by APC

APC Anaphase promoting complex Anaphase is initiated by the release of cohesins Catalyzed by Separase APC degrades securin which allows separase to become active which degrades the cohesin rings

Breakdown and reformation of the nuclear membrane

During prometaphase nuclear pore proteins and lamins are phosphorylated causing them to separate the membrane is broken down into vesicles During telophase the vesicles reform the membrane and pore proteins and lamins are dephosphorylated to reform the nuclear membrane
Once reformed nuclear proteins are pumped in and the chromosomes decondense allowing transcription to occur again
The cell is divided in 2 by the contractile ring

Cytokinesis in plant cells involves formation of the a few cell wall
Figure 18-35ac Essential Cell Biology ( Garland Science 2010)

Organelles must be divided too!

- Mitochondria and chloroplasts duplicate by division similar to cell division - They are present in large enough numbers to be equally distributed when the new cell is formed - The ER is continuous with the nuclear membrane it is released from the nuclear membrane but remains intact - It is cut in two during cytokinesis - The Golgi is fragmented during M and the fragments associate with the spindle microtubles by motor proteins hitching a ride! to the poles - Soluble proteins in the cytoplasm are inherited randomly during cytokinesis
But how is cell size and number controlled?

????????????????????????????
Dynamic balance between, cell growth, cell division and cell death
Apoptosis programed cell death

Cell suicide Controlled death process Initiates a regulated death process in response to cell signals Amount of normal apoptosis astonishing of nerve cells de during development Billions of gut and bone marrow cells die in humans each day Why????????? Separate structure?


Cell suicide Controlled death process Initiates a regulated death process in response to cell signals Amount of normal apoptosis astonishing of nerve cells de during development Billions of gut and bone marrow cells die in humans each day Why????????? Because those cells arent needed anymore?


To perfectly control organ size? Can resect the liver and it will regrow Expose human liver to phenobarbital liver will enlarge Remove drug and the liver will return to its natural size (within a week or so)
Organ size is regulated by a balance between the rate of cell birth and the rate of cell death
Apoptosis quick and clean
Necrosis messy! The result of injury Causes inflammation and damage to neighbors
Apoptosis quick, clean, environmentally safe!

No effect on surrounding cells cleaned up by phagocytes Organic material can be recycled

Apoptosis regulated by intracellular proteolytic cascade

Conserved
Caspases = family of proteases

Inactive precaspases cleaved in response to cellular signals
Initiate caspase cascades amplifying the response

They then break down nuclear lamina and other cytosolic proteins to dismantle the cell Irreversible! And tightly controlled

Apoptosis is regulated by Bcl-2 family of proteins
The grim reapers! pro-death Activated by death signals Release cytochrome C from mitochondria which activates caspases
Bear Grylles of the cell! Pro-survival! Block caspase activation By blocking release of Cytochrome C
Know some of these!

Bak and Bax stimulate formation of the apoptosome

But where do the life verses death signals come from?

Life/growth Cell Death
Dynamic balance between, cell growth, cell division and cell death
Cell must receive signals from their environment!

Unicellular organisms such as Bacteria and yeast grow as fast as they can Proliferation rate is controlled by: - Availability of nutrients - Space In multi-cellular organisms growth is controlled - Nutrients are needed by are not enough to cause cell division - Must receive signals, usually from surrounding cells in the form of soluble proteins (Pro) Survival factors suppress apoptosis Mitogens stimulate cell division by overriding cell cycle checkpoints Growth Factors stimulate cell growth (increase in size and mass) by promoting gene expression and suppressing protein degradation Not mutually exclusive many signaling molecules often stimulate more than one
Cell death adjusts the number of developing neurons to ensure sufficient target cells
Similar strategies used in other tissues during development and adulthood

Survival factors from other cells influence cell fate by binding to cell surface receptors

Mitogens stimulate cell division

Mitogens usually secreted proteins that bind to cell surface receptors and initiate cell signaling pathways to release cell cycle checkpoints (usually G1/S) Rb acts as transcriptional repressor Activated G1/S-CdK phosphorylates Rb releasing inhibition allowing transcription, translation and cell proliferation to occur

Growth factors stimulate cells to grow

Facilitate the growth of the cell by promoting protein synthesis and blocking degradation Some growth factors can stimulate growth and cell division Eg EGF PDGF NGF FGF
Figure 18-44 Essential Cell Biology ( Garland Science 2010) Figure 18-45 Essential Cell Biology ( Garland Science 2010)

Growth factors can also tell cells to stop growing!

Myostatin is an inhibitory growth factor that tells our muscles when to stop growing! These show cows breed for muscles mass where shown to have mutations of their myostatin genes


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Cell Biology: The Cell Division Cylce

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Essential Cell Biology

Chapter 18 The Cell Division Cycle

Copyright Garland Science 2010

Sarah E Golding PhD.

Compact Mitotic Chromosome

During S-phase the chromosomes are copied

Telomeres form caps at the ends of each chromatid

Steps of Cell Division

Figure 18-1 Essential Cell Biology ( Garland Science 2010)

Figure 18-2 Essential Cell Biology ( Garland Science 2010)

Cell-cycle control system

Critical checkpoints = molecular brakes

Sarah E Golding PhD.

Cell cycle check points

Nutrients and growth factors?

Cyclin-dependent Protein Kinases- Cdks

Cdks bind cyclins

Figure 18-4 Essential Cell Biology ( Garland Science 2010)

Kinases drive the cell cycle

Phosphorylation controls cyclin-CdK activity

Different cyclins control different cell cycle phases

Different cyclins control different cell cycle phases

Figure 18-10 Essential Cell Biology ( Garland Science 2010)

Remember: Ubiquitination is the cellular signal to degrade a protein

Figure 18-11 Essential Cell Biology ( Garland Science 2010)

The resting phase

Withdraw TEMPORARILY Actively growing Terminal Differentiated State

Sarah E Golding PhD.

Sarah E Golding PhD.

DNA Replication begins where??????

Sarah E Golding PhD.

S-Cdk involved in initiating DNA replication!

Sarah E Golding PhD.

How is S-phase initiated?

Cohesins tie together the replicated chromosome

ERRORS in chromosome segregation

Figure 18-15 Essential Cell Biology ( Garland Science 2010)

Sarah E Golding PhD.

M-phase is triggered by M-Cdk

You need to know this!

M-Cdk positively feeds back to further increase mitotic signals

Figure 18-18 Essential Cell Biology ( Garland Science 2010)

Condensins help condense chromatin

You should have this memorized

Sarah E Golding PhD.

You should have this memorized

Sarah E Golding PhD.

You should have this memorized

Form metaphase plate

Sarah E Golding PhD.

You should have this memorized

Sarah E Golding PhD.

Two transient cytoskeletal structures mediate M-phase in animal cells

Figure 18-20 Essential Cell Biology ( Garland Science 2010)

Chromosomal segregation is facilitated by the cytoskeleton

3 different types of Microtubules are involved

Figure 18-21 Essential Cell Biology ( Garland Science 2010)

The centrosome cycle

Forms the two poles of the cell

Figure 18-22 Essential Cell Biology ( Garland Science 2010)

Mitotic spindle assembly

Spindle bind via Kinetochores at the centromeres (one on each chromatid)

Metaphase chromosomes line up halfway between poles

Anaphase - Sister chromatids separate