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Flashcards in Tumour pathology 4 MW % + Deck (20)
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1

Normal cell cycle

Mitosis

• mechanism of cellular replication 

• nuclear division plus cytokinesis

Mitotic division generates 2 genetically identical daughter cells

Cell Cycle = time interval between mitotic divisions

2

Cell cycle diagram

  • G0: Exit from cell cycle. Stopped undergoing mitosis indefinitely
  • G1 : Cell growth. Metabolically active; duplicates organelles and cytosolic components and centrosome replication begins
  • S: DNA Replication
  • G2: Preperation for mitosis. Cell growth continues; enzymes and other proteins are synthesized; centrosome replication completed.

3

Cell cycle phases pic 2

4

Cell cycle control

•A cell must progress through cycle phases in the correct sequence in order to produce viable progeny

•DNA synthesis and mitosis must occur sequentially

Quality control ensures genetic fidelity (accuracy) in daughter cells

–each cell must receive a full chromosome complement

–mutations in DNA sequences must not pass on

 

 

5

Name the external and intrinsic factors in cell cycle control?

External factors

  • Hormones,
  • Growth factors
  • Cytokines
  • Stroma

Intrinsic factors

  • Critical checkpoints ⇒ Restriction point (R)

•prior to restriction point progress through G1 depends on external stimuli

•after restriction point progression becomes autonomous (free)

6

Phases of cell cycle

7

Other cell cycle checkpoints

  • If cell size inadequate - G1 or G2 arrest     
  • If nutrient supply inadequate - G1 arrest  
  • Essential external stimulus lacking - G1 arrest    
  • If the DNA is not replicated  - S arrest  
  • If DNA damage is detected - G1 or G2 arrest  
  • Chromosome mis-alignment - M-phase arrest  

8

What are the checkpoints?

  • System of cyclically active and inactive enzymes
  • Catalytic sub-unit activated by a regulatory sub-unit

-catalytic subunits are called cyclin-dependent kinases (CDKs) (Substrate)

  • regulatory sub-units are called cyclins (enzyme)
  • The active enzyme complex - CDK/cyclin complex  

9

Cyclins and cyclin-dependent kinases

• Different CDKs and cyclins operate at sequential stages of the cycle

• Active CDK/cyclin complexes phosphorylate target proteins

• Phosphorylation results in activation/inactivation of that substrate

• Substrates regulate events in the next cycle phase

 

10

Regulation of CDK activity

• CDKs are constitutively expressed in an inactive form

• Cyclins accumulate and are destroyed as cycle progresses

 

 

11

Regulation by CDK inhibitors (CKIs)

  •  INK4A family  bind to CDK4 and 6 and prevent association of these CDKs with their cyclin regulatory proteins 

• 2nd  family of CKIs -  CIP/KIP family

• These inhibitor molecules bind to cyclin/CDK complexes

12

The Retinoblastoma gene
 

•Encodes a 110 kDa phosphoprotein (pRb)  expressed in almost every cell of the human body

pRb is hypophosphorylated (partial phosphorylation)

•phosphorylation increases as cells progress through the cell cycle

•active cyclin D/CDK complexes phosphorylate pRb

 

13

pRb functon

• The most important target is E2F transcription factor

Hypophosphorylated/active  Rb inactivates E2F

Phosphorylated/inactive pRb loses affinity for E2F

•  Free E2F transcription factor activates vital target genes

E2F is a potent stimulator of cell cycle entry

Note:  Active pRb applies a brake to the cell cycle

14

Carcinogenesis

•Cancer is a genetic disease

•Carcinogenesis is caused by mutation of genetic material that upsets the normal balance between proliferation and apoptosis (cell death)

•uncontrolled proliferation of cells leads to tumours

•Only mutations in genes regulating  cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation

15

Carcinogenesis factors►

Non-lethal genetic damage

–Environmental agents

•Chemicals

•Radiation

•Oncogenic viruses

Inherited

 

16

Chemical carcinogenesis

purine and pyrimidine bases in DNA are critically damaged by various oxidizing and alkylating agents

•Chemical carcinogens or their active metabolites react with DNA forming covalently bound products (DNA adducts)

•Adduct formation at particular chromosome sites causes cancer

17

Radiation carcinogenesis

•purine and pyrimidine bases in DNA are critical cellular targets for radiation damage

•High-energy radiation is carcinogenic if received in sufficient doses

ultraviolet radiation (UV-B present in sunlight)

X-rays

Gamma radiation

 

18

Cell cycle dysfunction

The primary defect in cancer is Uncontrolled cell proliferation via cell cycle dysregulation

Many genes mutated in cancer regulate the cell cycle

• Two regulatory pathways frequently disrupted -

1. The cyclin D-pRb-E2F pathway

2. p53 pathway

 

Absent or inactive pRb releases the cell cycle brake 

19

P53 function

• Maintains genomic integrity

• p53 levels increase in damaged cells

-induces cell cycle arrest at G1

-facilitates DNA repair

• severe damage: p53-induced apoptosis (programmed cell death)

20

DNA damage response

• Cells with mutated p53 do not G1 arrest or repair damaged DNA

• Genetically damaged cells proliferate and form malignant neoplasms