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Molecular Basis Of Disease > Oncogenes And Tumour Suppressor Genes > Flashcards

Oncogenes And Tumour Suppressor Genes Flashcards

1
Q

State the major functional changes that occur in cancer?

A
  • Increased growth (angiogenesis)
  • Failure to undergo programmed cell death (apoptosis) or senescence
  • Loss of differentiation (including alterations in cell migration + adhesion)
  • Failure to repair DNA damage (including chromosomal instability)
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2
Q

What are the factors that regulate cell numbers?

A
  • Growth
  • Apoptosis
  • Differentiation
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3
Q

What are the 2 major types of mutated genes that contribute to carcinogenesis?

A
  • Oncogenes
  • Tumour suppressor genes
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4
Q

What is an oncogene?

A
  • Mutant form of proto-oncogene involved in the control of cell growth
  • Component of growth factor signalling pathways
  • Product formed has dominant and increased activity
  • Uncontrollable cell divison - cancer
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5
Q

What is a tumour suppressor gene and what happens if mutated?

A
  • A gene that controls cell division
  • Both genes for TS must be mutated
  • Causes Loss of function
  • Increased likelihood that a cell can become cancerous
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6
Q

How sarcoma was induced into a chicken

A
  1. Chicken with sarcoma in breast muscle
  2. Remove sarcoma and break up into small chunks of tissue
  3. Grind up sarcoma with sand
  4. Collect filtrate that has passed through fine pore filter, bacteria can’t pass through filtrate, viruses can pass
  5. Inject filtrate into young chicken
  6. Observe sarcoma in injected chicken
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7
Q

What is c-src + v-src?

A
  • C-src = Cellular oncogene
  • V-src = Proto oncogene altered form transduced by retrovirus
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8
Q

Describe the capture of c-src by retroviruses and what this leads to?

A
  • Virus acquires fragments of genes -> including C-src from host -> integrated with viral sequence -> creation of V-src -> Product is IC tyrosine kinase -> phosphorylates cellular proteins + uncontrolled growth -> cancer
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9
Q

What is Explanation of the oncogene hypothesis?
Final line is basically the hypothesis

A
  • Following infection, however, the v-sc oncogene was expressed at high levels in the host cell, leading to uncontrolled host cell growth, unrestricted host cell division, and cancer
  • Various agents, including radiation, chemical carcinogens, and, perhaps, exogenously added viruses, may transform cells by “switching on” the endogenous oncogenic information
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10
Q

Describe viral oncogenesis

A
  • DNA viruses causes lytic infection (causes the death of host) OR DNA replication with host (increases neoplastic transformation)
  • Viral oncogenes transmitted by DNA or RNA viruses
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11
Q

Describe how this differs between DNA viruses + RNA
viruses?

A
  • DNA: encodes proteins with environmental factors which initiates and maintains tumours
  • RNA: Integrate DNA copies of their genomes into the genome of the host cell (contain transforming oncogenes) causes cancer in host
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12
Q

Describe how oncogenes can become activated? (Steps)

A
  • Oncogenes code for proteins in growth factor signal transduction pathway
  • Genes captured (by virus) + altered
  • Via mutation, amplification/duplication, translocation + insertion
  • Alteration of at least one allele
  • Loss of response to growth regulatory factors
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13
Q

State the 4 types of proteins involved in the transduction of growth signals?

A
  • Growth factors
  • Growth factor receptors
  • Intracellular signal transducers + Nuclear transcription factors
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14
Q

Describe what the oncogenes code for within the Growth factor signal transduction pathways?

A
  • OG proteins function as growth factors (e.g.EGF), growth factor receptors (e.g. ErbB) + intracellular signalling molecules (Ras and Raf)
  • Regulates cell proliferation + survival in response to GF stimulation
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15
Q

Describe what ras and raf do

A
  • Ras + Raf -> activate ERK MAP kinase pathway -> induction of additional genes (fos) -> encodes potentially oncogenic transcriptional reg. proteins -> More proliferation -> Cancer
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16
Q

What are RAS proteins?

A

small GTPases bound to GDP in a neutral state

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17
Q

Describe the ras protein mechanism of action

A
  • Binding of EC GF signal
  • Increases recruitment of RAS proteins to receptor complex
  • Recruitment increases Ras to exchange GDP (inactive Ras) with GTP (active Ras)
  • Activated Ras initiates remainder of the signalling
    cascade (mitogen activated protein kinases)
  • Targets phos. - TF = increased expression of genes for cell growth + survival
  • Ras hydrolyzes TP to GDP fairly quickly, turning itself “off
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18
Q

Describe the oncogenic activaton of Ras protein with the specific mutations that occurs?

A
  • Point mutations in codons 12, 13 and 61 -> loss of GTPase activity normally required to return active RAS to the inactive RAS GDP -> Constitutive activation - hyperactivation of Ras + cell cycle
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19
Q

What cancer can arise from mutations in codon 12 of ras protein?

A
  • Val -> gly = bladder carcinoma
  • Cys -> gly = lung cancer
20
Q

Outline the MYC oncogene family

A
  • Oncogene family
  • C-MYC, MYCN + MYCL
  • Encodes c-Myc, N-Myc + L-Myc (TF)
  • Regulate transcription for 15% of genome
  • Identified in avian myelocytomatosis virus
21
Q

Outline The effects of the MYC oncogene family

A

Downstream effects
- Ribosome biogenesis, protein translation, cell-cycle progression + metabolism
- Cell proliferation, differentiation, survival, + immune surveillance

22
Q

Describe how MYC oncogene is activated

A

Encodes a helix-loop-helix leucine zipper TF that dimerizes with partner protein, Max, to transactivate (increase) gene expression

23
Q

Describe how MYC oncogene is overexpressed?

A
  • MYC activated via foreign transcriptional promotors -> chromosomal translocation -> deregulation of oncogene -> relentless proliferation
24
Q

Describe how MYC is activated in Burkitt’s lymphoma?

A
  • Epstein barr virus associated with BL -> high grade lymphoma (2-16 yrs)
  • BL: carries one of 3 chromosomal translocations involving Cr 2,14 OR 22 ->Region formed with section of Cr 8 -> Places MYC gene under regulation of Ig heavy chain -> deregulates c-myc expression
25
Q

Describe the logic of Tumour suppressor gene

A
  • A balance between growth promoting factors (Proliferation, Cell survival) and intrinsic tumour suppressor pathways (Cell cycle arrest, Apoptosis)
  • Like other well designed control systems, biological systems follow a similar logic component. Promoting a process must be counterbalanced by others that oppose the process tumour suppressor genes
26
Q

Describe features of Tumour suppressor genes

A
  • TSG products act as stop signs to uncontrolled growth, promote differentiation or trigger apoptosis
  • Regulators of cell cycle checkpoints (e.g. RB1), differentiation (e.g. APC) or DNA repair (e.g. BRCA1)
27
Q

Describe the loss of TSG function

A
  • Loss of TSG function requires inactivation of both alleles of the gene
  • Inactivation can be a result of mutation or deletion
  • TSG defined as recessive genes and ‘anti-oncogenes’
28
Q

What is retinoblastoma?

A
  • Rare childhood cancer
  • When immature retinoblasts continue to grow very fast and don’t turn into mature retinal cells
  • Eye contains a tumour which reflects light back in white colour (cat’s eye appearance - leukocoria)
29
Q

State the mutation of retinoblastoma

A
  • Two forms of the disease, familial (40%) and sporadic (60%)
  • The hereditary mutation is on chromosome 13 (13q14), the retinoblastoma 1 (Rb1) gene
30
Q

Describe the two-hit hypothesis of retinoblastoma

A
  • Rb gene = TSG - mutations of both functional copies required -> Loss of function mutation (point or small) -> inactivates TSG -> disrupts function
  • OR
  • Loss of heterozygosity -> inactivates the second copy of TSG -> A heterozygous cell receives a second hit in remaining functional copy -> thereby becoming homozygous for mutated gene.
31
Q

Describe the structure of the retinoblastoma protein RB structure and state its main binding partner?

A
  • The Rb gene family includes three members: Rb/(p105/110), p107 and b2/p130 - collectively known as pocket proteins
  • A transcriptional co factor that can bind to TF
  • N-terminus, large pocket (small pocket (spacer) + C-terminus)
  • Main binding partner is the E2F TF, interacting with the large pocket
32
Q

Describe the main function of Rb within the cell cycle?

A
  • Regulates cell cycle
  • Inhibit G1 to S phase transition
33
Q

What can lead to the phosphorylation of PRb?

A
  • Cyclin D is the first cyclin to be synthesized and drive progression through G1 together with cdks4/6
  • The G1 checkpoint leads to the arrest of the cell cycle in response to DNA damage
  • Cyclin D (key substrate), E families + cdks phosphorylate RB
34
Q

Describe the function of the retinoblastoma protein

A
  • PRb regulates activity of E2F TF (expresses genes for S phase)
  • Rb activity regulated via phosphorylation
35
Q

Describe the activity of the retinoblastoma protein

A
  • Dephosphorylated -> active -> Remains bound to E2F -> blocks progression to S phase and inhibits cell proliferation
  • Hyperphosphorylated (via EC physiological signals) -> Inactive -> E2F released -> migrates to nucleus to induce transcription for Genes of S phase -> Cell cycle progression from G1 to S
36
Q

Describe ways in how Rb can become inactivated and within retinoblastoma?

A
  • Phosphorylation, mutation or viral oncoprotein binding
  • Retinoblastoma -> pRb -> mutations OR partial deletions
  • Viral inactivation found in small DNA tumour viruses -> disrupting E2F binding or destabilisation of Rb
  • Cancer cells -> RB phosphorylation deregulated -> E2F TF induces deregulation of cell cycle -> cell move through G1 into S + not subjected to usual check
37
Q

Describe the role of P53 and features of when P53 mutation arises from tumour cell genome?

A
  • TSG -> Senses DNA damage + regulates cell death/apoptosis
  • Frequent mutation of P53 - tumour cells try to eliminate P53 function before thriving
38
Q

Describe the structure of a P53 gene?

A

Contains: Amino transactivation domain, a central DNA binding Domain, a tetramerization Domain + carboxyl regulatory Domain -> TF

39
Q

What regulates P53 levels?

A
  • Normally P53 levels decrease
  • Kept via MDM2 protein - ubiquitin ligase (oncogene)
40
Q

How does this occur?

A
  • MDM2 binds p53
  • Complex formed in nucleus
  • MDM modifies the carboxyl terminus of p53 + targets it degradation via proteasome
  • Wildtype p53 has a short 20 min half life
41
Q

How is P53 tumour suppressor gene activated?

A
  • Stress signals sensed by kinases
  • Phosphorylation of p53
  • Activated p53 disrupts the interaction between it + MDM2
  • Regulates genes involved in DNA damage repair, apoptosis and cell cycle arrest
42
Q

State an example of a stress signal that induces activation of Ras?

A

ionizing radiation signals through two kinases ATM/ATR activate oncogenes (ras) induce activity of p14arf responsible for sequestering MDM2.

43
Q

State factors that can be targeted for P53 mutation/therapeutic strategies?

A
  • Mutational inactivation (>1/2 of human cancer carry loss of function of p53), correcting P53 mutation, restoring wild-type P53 function by targeting its regulators
  • 95% of mutations were detectable within the DNA-binding domain
44
Q

Describe therapeutic strategies for TP53?

A
  • Gene therapy
  • Retroviruses integrate in stable form into genome of infected cell - retrovirus-mediated gene transfer of wildtype TP53 into human lung tumour cell lines + xenograft model - inhibition of tumour cell growth
  • Use of inhibitors
45
Q

State and describe inhibitors used for P53?

A
  • PRIMA-1 - Restores mutant P53 by modifying thiol groups in core domain of protein
  • Nutlin - Potent MDM2 antagonist
  • RITA - binds P53 + restores mutp53 activity
  • CRM1 inhibitor - nuclear accumulation of P53

Molecular Basis Of Disease (30 decks)

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