Dr Zahid AzeemAssistant ProfessorBiochemistryAJK Medical CollegeMBBS-Batch 2019 --- CMB Module

Define Cell CycleCell reproduces by performing orderly sequence of

events in which it duplicates its contents and then divides in two. This type of duplication and division is called Cell Cycle.

Major QuestionsTo explain how cells reproduce, we therefore have to

consider three major questions: (1) How do cells duplicate their contents?(2) How do they partition the duplicated contents and

split in two?(3) How do they coordinate/regulate all the machinery

that is required for these two processes?

1- How do cells duplicate their contents?

Five Phases of the Cell CycleFive Phases of the Cell Cycle1- 1- GG11 - primary growth phase - primary growth phase

2- S – synthesis; DNA replicated2- S – synthesis; DNA replicated3- G3- G22 - secondary growth phase - secondary growth phase

4- M – mitosis4- M – mitosis5- C - cytokinesis5- C - cytokinesis

M-phase

Interphase

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InterphaseDuring all of interphase, a cell generally continues to

transcribe genes,synthesize proteins, and grow in mass. Together, G1 and G2 phases provide additional time

for the cell to grow and duplicate its cytoplasmic organelles

if interphase lasted only long enough for DNA replication, the cell would not have time to double its mass before it divided and would consequently shrink with each division.

In some animal embryos, for example, the first cell divisions after fertilization (called cleavage divisions) serve to subdivide a giant egg cell into many smaller cells as quickly as possible.

In these embryonic cell cycles, the G1 and G2 phases are drastically shortened, and the cells do not grow before they divide.

Timelines for Cell Cycle PhasesG1-phase 10-12 hours S- phase 8-10 hoursG-2 phase 4-6 hourM-Phase 1-2 hours Total 24 hour

This time calculation and frequency is true for majority of cells. Cell cycle can be very short as in embryonic cells.

Frequency of cell divisionFrequency of cell division varies by cell type

1- embryocell cycle < 30 minute

2- skin cellsdivide frequently throughout life12-24 hours cycle

3- liver cells retain ability to divide, but keep it in reservedivide once every year or two

4- mature nerve cellsdo not divide at all after maturitypermanently in G0

Interphase - GInterphase - G11

11stst growth stage after cell division growth stage after cell divisionCells mature by making more cytoplasm & Cells mature by making more cytoplasm &

organellesorganellesCell carries on its normal metabolic activitiesCell carries on its normal metabolic activities

Interphase – S StageInterphase – S Stage1- Synthesis stage1- Synthesis stage

2- DNA is copied or replicated2- DNA is copied or replicated

Two Two identical identical copies of copies of DNADNA

Original DNAOriginal DNA

Interphase – GInterphase – G22 Stage Stage

22ndnd Growth Stage Growth StageOccurs after DNA has been copiedOccurs after DNA has been copiedAll cell structures needed for division are made All cell structures needed for division are made

(e.g. centrioles)(e.g. centrioles)Both organelles & proteins are synthesizedBoth organelles & proteins are synthesized

What the cell looks likeWhat the cell looks like

Animal Cell

Second Question (2) How do they partition the duplicated contents and split in two?

Four Mitotic StagesFour Mitotic Stages

ProphaseProphaseMetaphaseMetaphaseAnaphaseAnaphaseTelophaseTelophase

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Kinetochore FiberKinetochore Fiber

ChromosomeChromosome

What the cell looks likeWhat the cell looks like

What’s happeningWhat’s happening

CytokinesisCytokinesis

Means division of the cytoplasmMeans division of the cytoplasmDivision of cell into two, identical halves called daughter Division of cell into two, identical halves called daughter

cellscells In plant cells, cell plate forms at the equator to divide cellIn plant cells, cell plate forms at the equator to divide cellIn animal cells, cleavage furrow forms to split cellIn animal cells, cleavage furrow forms to split cell

Daughter Daughter CellsCells

DNA CopiedDNA Copied

Cells Cells MatureMature

Cells prepare for Cells prepare for DivisionDivision

Cell Divides into Identical Cell Divides into Identical cellscells

G1

G1 checkpoint

G1

G0

If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in the cell cycle.

If a cell does not receive a go-ahead signal at the G1 checkpoint, the cell exits the cell cycle and goes into G0, a nondividing state.

Question -3How do they coordinate/regulate all the machinery that

is required for these two processes?

How is progress through cell cycle regulated?

“Cell-cycle control system”

The ‘Checkpoint’ model

How are they controlled? -- intracellular and extracellular signals

What are the effectors -- lots of kinases & phosphatases

How is cell division and growth regulated?

Growth factors-- stimulate cell growth

Mitogens-- trigger cell division-- e.g., EGF, phytoestrogens

Survival signals-- disable apoptotic mechanisms

What did study of frog embryos reveal about the control system?

Be sure to read How we know

Frog egg cytoplasmic transfer experiments

Something in the cytosol triggers mitosis

-- called MPF

Activity of MPF oscillates during the cell cycle

What is MPF?

What do we know about MPF & cyclin?

MPF is a cyclin bound to a Cdk ‘cyclin-dependent protein kinase’

= M-Cdk

Several Cyclins and Cdks -- regulate different cell cycle events

Table 18–2 The Major Cyclins and Cdks of Vertebrates

Cyclin–Cdk Complex Cyclin Cdk partner G1-Cdk cyclin D Cdk4, Cdk6 G1/S-Cdk cyclin E Cdk2 S-Cdk cyclin A Cdk2 M-Cdk cyclin B Cdk1

How is cyclin-CDK activity regulated?

Two processes

1. Synthesis & destruction of cyclin

-- ubiquination-- proteasomes

2. Inactivation & activation-- Activating/inhibitory Kinases/phosphatase

-- Pos feedback rapid activation

How do cyclin-cdk’s trigger cellular events?

S-Cdk triggers DNA replication-- activates replication origins-- blocks reactivation

What does activated M-CDK do?

1) Phosphorylates H1 histone (triggering C’some condensation)

2) Disassembly of nuclear lamina3) Changes behavior of microtubules

-- phosphorylates MAPs

How is cyclin-Cdk coupled to checkpoint control?

Tumor suppressor genes-- inactivation can dispose cell toward tumor formation

-- P53, P21 and Rb are all TSGs

-- loss of both alleles necessaryWhy?

P53 can also trigger apoptosis

Figures 18-14 + 18-15

Regulation of Cell CycleWhat are the cell cycle checkpoints?

Regulation of Cell CycleHow does the active

MPF bring about events of mitosis intiation?

Regulation of Cell CycleHow is G1 checkpoint controlled?

Regulation of Cell Cycle

Cell Growth and CancerHow can growth factors inhibit cell division?

Alterations in what kinds of genes lead to development of cancer?

How do oncogenes cause cancer?

Cell Growth and CancerHow does the p53

tumor suppressor gene work?

Thanks

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