Oncogenes and Tumour Supressors Flashcards Preview

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Flashcards in Oncogenes and Tumour Supressors Deck (49)
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1

Recap: What is a hallmark?

A characteristic a normal cell has to acquire in order to become a tumour cell

2

Which two hallmarks of cancer are linked to oncogenes and tumour supressors?

Sustaining proliferative signalling = oncogene

Evading growth suppression = tumour suppressor proteins

3

Summarise the major functional changes which occur in cancer

  1. Increased growth (loss of regulation, stimulation of environment promoting growth e.g angiogenesis)
  2.  Failure to undergo programmed cell death apoptosis or senescence
  3. Loss of differentiation (including alterations in cell migration and cell to cell adhesion (forms hallmark for metastases)
  4. Failure to repair DNA damage (including chromosomal instability)

4

What is an oncogene? (Myc + Ras)

 An oncogene is a mutant form of the normal gene (proto-oncogene) which can promote cell proliferation and are permanently active in cancer 

They will normally encode for components of growth factor signalling pathways, when mutated they will produce products at a higher quantities or altered products will act in a dominant manner 

 

(Oncogenes can be counteracted by tumour suppressor genes if they are strong enough) 

5

Describe the historical perspective of oncogenes and their discovery

  • Francis Peyton Rous used cell filtrate from a large tumour on chicken chest muscle to induce chicken sarcomas in healthy chickens .
  • Found that the carcinogenic agent was small enough to pass through a filter (which excluded viruses) 
  • Concluded that a virus must be responsible 
  •  Discovered that oncogenic transformation by this virus is caused by an extra gene which is contained in its genome called = oncogene (v-src)
  • The Rous sarcoma viral gene is actually a host gene which has been kidnapped by the virus and transformed into an oncogene

6

Why does Rous sarcoma virus cause cancer (sarcoma)? 

The virus contains a proto-oncogene (c-src) which acquires fragments of genes from host integration sites, resulting in the creation of a viral oncogene (v-src). 

 

This causes oncogenic transformation and abnormal grwoth in host cells. 

7

What is v-src? 

An oncogene coding for 60kDa intracellular tyrosine kinase which can phosphorylate cellular proteins and affect growth. 

 

(c-src proto-oncogene will acquire fragments of genes from host integration sites = viral oncogene v-src) 

8

How do DNA viruses cause oncogenesis? 

DNA viruses will cause lytic infection leading to death of the cellular host or replicate their DNA along with that of the host promoting neoplastic formation 

DNA viruses will encode various proteins along with environmental factors which can initiate and maintain tumours 

9

How can RNA viruses cause oncogenesis? 

Integrate RNA copies of their genome into the genome of the host cell and as these contain transforming oncogenes they induce cancerous formation of the host 

 

E.g EBV will produce its own oncogene called latant membrane protein (LMP-1) causing Burkitts Lymphoma, B-cell Lymphoma, Nasopharyngeal carcinoma 

10

How can oncogenes be activated?

Oncogenes become activated due to alterations in the proto-oncogene sequence 

  • Mutations 
  • Insertions 
  • Amplification 
  • Translocation 

These alterations can cause a loss of response to growth regulatory factors (only one allele needs to be altered) 

11

What do proto-oncogenes encode? 

They are normal signal transduction pathways encoding components of the growth factor signal transduction pathway 

12

What are the products of oncogenes? 

Proteins involved in the transduction of growth signals 

  • Growth factors (EGF) 
  • Growth factor receptors (ErbB)
  • Intracellular signal transducers (Ras and Raf)  
  • Nuclear transcription factors 

 

13

What can oncogenic proteins act as? 

The oncoproteins produced by oncogenes will function as elements of the signalling pathways which regulate cell proliferation and survival (in response to growth factor stimulation) 

Oncogene proteins will act as:

  • Growth factors e.g EGF
  • Growth factor receptors e.g ErbB
  • Intracellular signalling molecules e.g Raf and Ras  

14

What pathway do Ras and Raf activate? 

Ras and Raf will activate the ERK/MAP kinase pathway leading to induction of additional genes (e.g fos) that encode potentially oncogenic transcription of regulatory proteins 

15

Describe the discovery of the Ras oncogene family

Ras genes were identified from two cancer causing viruses -

  • Harvey Sarcoma and Kirsten sarcoma
  • They were originally discovered in rats hence called Rat sarcoma

16

What are Ras proteins? 

Small GTPases which are bound to GDP in their inactive state 

 

-

17

How can mutated Ras proteins cause oncogenesis? 

 

  • Ras proteins become mutated through point mutations 
    • In codon 12, 13, 61 
  • CONSEQUENCE = loss of GTPase activity required to return active Ras to inactive Ras GDP = hyperactive Ras (constitutive activation) 

18

What occurs as a consequence of codon 12 point mutation in Ras?

Glycine to Valine = bladder carcinoma

Glycine to Cysteine = lung cancer

19

Describe the normal RAS mechanism

  1.  Binding of extracellular growth factor signal 
  2. Promote recruitment of Ras proteins to receptor complex 
  3. Recruitment promotes Ras to exchange GDP (inactive Ras) with GTP (active Ras) 
  4. Activated Ras then initiates the remainder of the signalling cascade (protein kinases phosphorylation) 
  5. These kinases will phosphorylate targets (e.g TRANSCRIPTION FACTORS) 
  6. This will promote the expression of genes important for cell growth and survival 

Ras will normally hydrolyse GTP to GDP fairly quickly (turning itself off) however in mutated form it is hyperactive 

 

 

20

Describe the Myc oncogene family

  • Myc oncogene family consists of 3 members
    • C-MYC, MYCN and MYCL which encode c-Myc, N-Myc and L-Myc respectively
      • Belong to a family of TF's which regulate transcription of 15% of the genome 
    • These were originally discovered in the avian myelocytomatosis virus (AMV)

21

What are the major effects of Myc? 

Downstream effectors include 

  • Ribosomal biogenesis 
  • Protein translation 
  • Cell cycle progression + metabolism 
  • Survival and immune surveillance 

22

What is the role of Myc in cancer?

The Myc oncogene will be overexpressed/activated in majority of human cancers by chromosomal translocation. 

Myc will come under the control of foreign transcriptional promoters causing it to become activated 

= deregulation of the oncogene + drives relentless proliferation 

23

How does Myc perform its role? 

Encodes a helix-loop-helix transcription factor which dimerizes with its partner protein Max, to transactivate gene expression 

24

What is the link between burkitts lymphoma and Myc?

  • Burkitts lymphoma is associated with Epstein Barr Virus
  • Myc is commonly activated in Burkitt's Lymphoma
  • All the BL cases carry one of the three characteristic chromosomal translocations 
    • Myc gene is under foreign regulation of the Ig heavy chain
      • This causes c-myc expression to be deregulated 
  • In all three translocations a region from one of these chromosomes is fused to a section of chromosome 8, switching MYC on 

25

Describe another example of chromosomal translocation which is responsible for oncogenes

  • CML patients carry the Philadelphia chromosome o t(9;22)(q34;q11) generating the BCR-ABL fusion protein
  • As a result of this translocation the tyrosine kinase activity of the oncogene ABL is constitutive = abnormal proliferation •
  • Therapeutic strategies for CML = Imatinib (Gleevac) 95% remission in early stage patients
    • This is a tyrosine kinase inhibitor

26

What are tumour suppressors genes?

A gene whose normal activity prevents formation of cancer (acts like the car brake) usually through inducing cell cycle arrest or apoptosis. 

  • This loss of tumour supressor gene function requires 2 hits (one in each allele) to have an effect on the protein and cause the tumour suppressor to lose its function
    • Hence defined as recessive genes

 

 

27

Describe the historical perspective of tumour suppressor genes and their discovery

  •  Fusion of normal cells with tumour cells yielded hybrid cells containing chromosomes from both parents 
  • These cells were not capable of forming tumours 
  • Genes derived the normal parents acted to inhibit and suppress tumour development 
  • The first tumour suppressor gene was identified by studies of retinoblastoma – a rare childhood eye tumour

28

What are examples of tumour suppressor genes?

Examples of tumour suppressors are known as anti-oncogenes (they can counteract their activity)

Tumour suppressor gene products will act as stop signs to uncontrolled growth, promote differentiation or trigger apoptosis

Therefore they are usually regulators of cell cycle checkpoints E.g RB1, differentiation (APC), or DNA repair (BRCA1)

29

What is retinoblastoma? 

  • This is a rare childhood cancer that affects 1 in 20,000 children 
  • Immature retinoblasts will grow very fast and do not turn into mature retinal cells 

 

30

What does the eye of someone with retinoblastoma appear like?

  • An eye which contains a tumour will reflect light back in a white colour
    • This is often called cats eye appearance (technical term leukocoria)

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