week 3 dr zain, cell cycle.ppt

8/10/2019 WEEK 3 Dr zain, Cell cycle.ppt

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The Cell Cycle

By the end of the lecture, you will be able to:

Define cell cycle

Describe the phases of cell cycle

Identify the check points in cell cycle and

elaborate their significance.

Describe the role of cyclins other

molecules in the regulation of cell cycle.


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Chromosome

duplication

(including DNAsynthesis)

Centromere

Sister

chromatids

Separation

of sister

chromatids


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Sites of mitosis

In the foetus, babies and growing children mitosis occurs in

most tissues. In adults, however, most tissues do not proliferate but mitosis

occurs regularly at the following sites:

Red bone marrowfor production of blood cells

(erythropoiesis)

Lymphoid tissue - formation of lymphocytes (lymphooiesis)

Testesfor spermatogenesis (production of spermatozoa)

Epidermis - replacement of superficial skin cells

Hair follicles - hair growth

Gastro-intestinal tract - renewal of epithelium


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In adults mitosis does not normally occur in:

Neurons Muscle cells

In the adult, many cells are normally quiescent but may be

stimulated to undergo mitosis. Such cells are said to be in G0

phase of the cell cycle.

Fibroblastsin connective tissue are normally quiescent but are

stimulated into the cell cycle following tissue injury.

Hepatocytes(liver cells) normally have a very slow rate of

turnover. The liver contains some cells with large tetraploid (4n)nuclei (cells in G2) and binucleate cells (cells that have not yet

undergone cytokinesis).


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Cell type Approximate life span

Skin cells 24 hour- 2 weeks

RBCs 120 days

hepatocytes 300-500 days

Intestinal lining cells 4-5 days

The rate of cell division varies with the need for those

types of cells.


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The Cell Cycle

Cell Cycle = Ordered sequence of events (M, G1, S and G2phases) in the life of an eukaryotic cell, from division of a

parent cell into two daughter (progeny) cells

When mammalian cells are not inhibited and are

reproducing as rapidly as they can, this life cycle is as littleas 10-30 hours.

It is terminated by a series of events called mitosis that

cause division of the cell into two daughter cells

The actual stage of mitosis lasts only for 30 min---1 h. whichmeans that the cells spend more than 95% of its life cycle in

apparently (under light microscope) dormant state so

called the interval between mitosis called inter-phase


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This mitosis=M phaseinclude two visually events:

1. when the nucleus divides termed mitosis

2. when the cell physically splits in two termed cytokinesis The long period between one M phase and next M phase (

average 23 hours This period is called:inter-phase

During inter-phase,

S phase(S = synthesis : DNA replication

Ensuring that when it does divide at the end of M phase each of

the newly created daughter cells will contain a full set of genes

After mitosisand before DNA synthesis begins, there is a gap

phase called G1: i.e between Mand Sphase

After DNA synthesis there is interval between the end of S

phase and the beginning of next Mphase another gap called G2


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Phases of the Cell Cycle

Cell cycle consists of:

Mitotic (M) phase

G1 phase (first gap)

S phase (synthesis) G2 phase (second

gap)


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Interphase

ATP is synthesized.

Damaged parts are repaired.

Wastes are excreted.

Proteins are made. Organelles are formed.

Chromosomes are copied.

Specialized tasks are performed .


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1. Prophase

Longest phase.Chromatin coils.

Nucleus disappears.

Centrioles migrate.

Spindle forms.

Mitosis1. Prophase

2. Prometaphase

3. metaphase4. Anaphase

5. Telophase

6. Cytokinesis


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Metaphase

1. Breakdown of the nuclear envelope

2. Kinetochores become fully matured on the centromeres of the

chromosomes.

3. The mitotic spindles gain access to the mature kinetochores.

4. Sister chromatids are captured by microtubules

5. Once they have captured chromosomes, the kinetochore mictrotubles

begin to exert force on the chromosomes, moving them.

Prometaphase


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Anaphase

Centromere splits.

Chromatids are separated.

Chromatids are now calledchromosomes.

Telophase

Cytoplasm divides.

Nucleus reappears.

Chromosomes uncoil.


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Cytokinesis The cytoplasm divides and two identical

daughter cells are formed.


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Checkpoint control system

3 major checkpoints: G1/S

can DNA synthesis begin?

G2/M has DNA synthesis been

completed correctly?

commitment to mitosis

spindle checkpoint

are all chromosomes attachedto spindle?

can sister chromatids separate

correctly?


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G1/S checkpoint

G1/S checkpoint is most criticalprimary decision point

restriction point

if cell receives GO signal, it divides internal signals: cell growth (size), cell nutrition

external signals: growth factors

if cell does notreceive

signal, it exits cycle &

switches to G0phase

non-dividing, working state


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G0phase

M

Mitosis

G1

Gap 1

G0

Resting

G2

Gap 2

S

Synthesis

G0phasenon-dividing, differentiated state

most human cells in G0phase

liver cells

in G0, but can be called

back to cell cycle by

external cues

nerve & muscle cells

highly specialized

arrested in G0& can

never divide


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How do cells know when to divide?cell communication signals

chemical signals in cytoplasm give cue

signals usually meanproteinsactivators

inhibitors

Activation of cell division

experimental evidence: Can you explain this?

G h d i l


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Go-aheadsignals

Protein signals that promote cell growth &division

internal signals promoting factors

external signals

growth factors

Primary mechanism of control

phosphorylation kinaseenzymes :- activates cell signals

Cell cycle controlsCyclins regulatory proteins, its levels cycle in

the cell cycle

Cdks cyclin-dependent kinases

phosphorylates cellular proteins

activates proteins

Cdk-cyclin complex - triggers passage through

different stages of cell cycle activated Cdk

inactivated Cdk


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Degraded

cyclinG2

checkpoint

Cdk

Cyclin isdegraded

MPFCyclin

Cdk

Molecular mechanisms that help regulate the cell cycle


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Cdk / G1cyclin

Cdk / G2cyclin (MPF)

G2

S

G1

CM

G2/ M checkpoint

G1/ S checkpoint

APC

ActiveInactive

ActiveInactive

Inactive

Active

mitosis

cytokinesis

MPF= Mitosis

Promoting Factor

APC= Anaphase

Promoting Complex

Replication completed

DNA integrity

Chromosomes attached atmetaphase plate

Spindle checkpoint

Growth factors

Nutritional state of cellSize of cell


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External signals

Growth factors

coordination between cells

protein signals released by body cells that

stimulate other cells to divide

density-dependent inhibition

crowded cells stop dividing each cell binds a bit of growth factor

not enough activator left to trigger division in

any one cell

anchorage dependence

to divide cells must be attached to a substrate touch sensor receptors

E ample of a Gro th Factor


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Example of a Growth Factor

Platelet Derived Growth

Factor (PDGF)

made by platelets in bloodclots binding of PDGF to

cell receptors stimulates

cell division in fibroblast

(connective tissue) Woundshealing

Other Extrinsic factors - interaction with other cells

Growth factors are necessary for stimulating cell proliferation . Some

growth factors act mainly, but not exclusively, on certain cells as indicatedby their names. e.g. Platelet derived growth factor (PDGF)

Epidermal growth factor (EGF)

Fibroblast growth factor (FGF)

Transforming growth factor (TGF)

Interleukin-2 (IL-2).


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Cancer & Cell Growth Cancer is essentially a failure

of cell division control system or checkpoint

unrestrained, uncontrolled cell growth

What control is lost?

lose checkpoint stops

genep53plays a key role in G1

/S restriction point

p53 protein halts cell division if it detects damaged DNA

Through :

stimulates repair enzymes to fix DNA

forces cell into G0

resting stage

keeps cell in G1arrest

causes apoptosis of damaged cell

ALLcancers have to shut down p53activity

D l t f C


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Development of Cancer

1. Unlimited growth

Turn ongrowth promoter genes2. Ignore checkpoints

Turn off tumor suppressor genes(p53)

3. Escape apoptosis

Turn offsuicide genes

4. Immortality = unlimited divisions

Turn onchromosome maintenance genes

5. Promotes blood vessel growth

Turn onblood vessel growth genes

6. Overcome anchor & densitydependence

Turn offtouch-sensor gene

Cancer develops only after a cell experiences ~6 key mutations hits)

these hits caused by mutation, Mutations in cells can be triggered by

Cigarette smoke

Pollution

Age

Genetics

UV radiation

Chemical exposure

Radiation exposure

Heat


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Clinical Applications

Chemotherapy of cancers:Interrupting the cell cycle and preventing the cancer cells from

proliferating.

They are:

1. Cell cycle-specific (CCS): Act specifically on tumor cells

undergoing cycling)i. Usually more active in a specific phase of the cell cycle.

ii. Particularly effective when large proportion of tumor

cells are proliferating.

OR2. Cell cycle-non-specific (CCNS): Kill tumor cells in both

cycling and resting phases of the cell cycle.


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Clinical Applications

Side effects:

The normal sites of cell proliferation are affected resulting in:

hair loss

intestinal disorders

anaemia infertility

week 3 dr zain, cell cycle.ppt

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