Week 13 - Cancer Genetics Flashcards Preview

Molecular Genetics > Week 13 - Cancer Genetics > Flashcards

Flashcards in Week 13 - Cancer Genetics Deck (23)
Loading flashcards...
1

What is Cancer?

A disease caused by an uncontrolled division of abnormal cells in a part of the body

2

Types of Tumors

Benign - a mass of cells that lacks the ability to invade neighbouring tissue or metastasize
Malignant - invades surrounding tissues and is usually capable of producing metastasis

3

Requirements of a Cancer Cell

Sustain proliferative signalling
Evade growth suppressors
Avoid immune destruction
Enable replicative immortality
Tumor-promoting inflammation
Activating invasion
Inducing angiogenesis
Genome instability and mutation
Resisting cell death
Deregulating cellular energetics

4

Oncogene

Mutated and/or overexpressed version of a normal gene (proto-oncogene) that when dominant can release cell from normal restraints of growth
This with other changes converts cell into tumor cell

5

Internal and External Factors that cause Cancer

Internal
- faults in DNA repair mechanisms
- inherited mutations
- epigenetic factors
External
- chemical mutagens
- radiation
- infection e.g. virus

6

Proto-oncogene

Normal genes that are present in normal cells that are involved in normal growth and development

7

Retroviral Life Cycle

Enveloped ss RNA virus
Goes through reverse transcription making viral cDNA
Integrated into genome
Transcription and translation
Produces viral RNA and along with protein synthesis makes more viral RNA

8

How does an oncogene in a retroviral genome differ from proto-oncogene?

Viral oncogene transcribed under control of viral promoter
Therefore oncogenes expressed at higher levels than proto-oncogene and sometimes transcribed in inappropriate cell types

9

RNA Tumor Viruses

Retroviruses
Replicate via DNA intermediate
Normal retrovirus consists of:
- duplicate RNA genomes
- icosahedral viral core
- envelope made from host cell membrane and viral glycoproteins

10

Ways that RNA Tumor Viruses cause cancer

1. Some RNA tumor viruses have an extra gene in their genome
- this viral gene is the transforming factor that causes infected cells to become cancerous
2. Cis-acting retroviruses
- transformation caused by random integration into host gene such that LTR in close proximity to growth regulating genes
- cause endogenous cellular gene to be overexpressed
- leads to loss of control of cell proliferation
- take longer to develop transducing viruses
3. Trans-acting retroviruses
- cause up-regulation of cellular proto-oncogenes through action of viral transcription
- long latency period between infection and tumor development

11

DNA Tumor Viruses

DNA genome
Normally DNA viruses:
- enter host cell and produce protein that activates host transcription
- use host protein to replicate genome and create large number of progeny virus
- lyse the cell releasing new virus particles
Sometimes viral DNA becomes integrated into cell before its replicated and viral proteins expressed
These viral proteins interact with host proteins preventing host protein from functioning correctly

12

SV40

DNA tumor virus
Large T antigen - inactivates cell cycle arrest genes and inhibits programmed cell death
Binds RB and p53
Therefore SV40 proteins inactivate cellular tumor suppressors

13

Cervical Cancer

Abnormal cell growth on cervix
Caused by HPV infection
Pre-cancerous changes long before invasive cancer develops

14

Gardasil

Protects against types of HPV
Prevents infection; doesn't treat existing infection
Highly effective
Side effects
- fatigue
- paralysis
- blindness

15

How do proto-oncogenes become oncogenes?

Through number of mutations anywhere on a signalling pathway
Growth factors
- become activated by transcriptional activation of gene leading to overproduction
Growth factor receptors
- become constitutively activated
Signal transducers
- become constitutively activated
Transcription factors
- deregulation
Regulators of cell death

16

RAS Oncogene

Super family of membrane associated G-coupled proteins
Participate in proliferation, motility and survival
When mutated they lead to deregulated cell proliferation, survival, invasion and angiogenesis
Mutations occur at codon 12
Proto-oncogenic form of RAS - GGC to Gly
Oncogenic form of RAS - GTC to Val

17

Guanine Nucleotide Exchange Factors (GEFs)

Proteins that activate monomeric GTPases by stimulating release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP)

18

Tumor Suppressor Genes

Prevent cells with mutations from becoming cancers by causing them to stop proliferating
Allows DNA repair mechanisms to fix the mutated DNA
or by inducing them to commit suicide if the damage is too great
Inactivation of TSGs leads to cancer
Inactivation of TSGs is a loss of function mutation - recessive

19

p53 Tumor Suppressor Gene

p 53 protein produced by p53 gene
It inhibits cell proliferation and transformation
Activated in response to multiple cellular stresses
In normal cells the level of p53 is low and is regulated by MDM2
Attachment of MDM2 to p53 leads to destruction of p53 in the cell

20

Inactivation of p53

Feature of more than 50% of all human cancers
Can be caused by point mutations which can inhibit p53 from binding to transcription factor binding sites on DNA

21

RB Tumor Suppressor Gene

Normal RB protein (pRB) switches from active to inactive
depending on the stage in the cell-cycle
Controls availability of the E2F transcription factor in G1 to S checkpoint
With no RB, E2F produces protein which helps development of cancer cells
Mutations anywhere in the RB gene lead to inability to downregulate these transcription factors
Leads to transcription at wrong times

22

Apoptosis

Programmed cell death
Fundamental cell process involved in:
- development
- maintenance of tissue homeostasis
- elimination of damaged cells
Two pathways leading to this:
1. Extrinsic
- death receptors on outside of cell are activated
2. Intrinsic
- mitochondria releases Cytochrome C in response to stress signals
Both pathways lead to activation of a series of enzymes called caspases
Caspases are cysteine proteases

23

What happens when Apoptosis goes wrong?

Can cause:
- neurodegenerative disease
- diabetes
- cancer
Apoptosis can be blocked by both oncogenes and faulty tumor suppressor genes