Molecular biology and the diagnosis and treatment of cancer Flashcards
Cancer can be caused by:
physical carcinogens
chemical carcinogens
biological carcinogens
physical carcinogens:
ultraviolet and ionizing radiation.
chemical carcinogens:
asbestos and tobacco smoke.
biological carcinogens:
infections from certain viruses, bacteria or parasites.
What does HER stand for?
Human Epidermal Growth Factor Receptors
What are HERs?
a family of structurally-related cell surface protein
4 HER families
HER1 (EGFR/ERB1)
HER2 (ERB2/NEU)
HER3 (ERB3)
HER4
What is the structure of HERs
Extracellular ligand-binding domain
Intracellular tyrosine kinase domain
What do HER proteins undergo? Which one if the exception?
HER proteins undergo a conformational change
upon ligand binding that is essential for dimerization and signaling
HER2 does not undergo this
What primes the receptor for activity?
The ligand
What happens once the ligand binds?
The receptor can either homo or heterodimerise.
This stimulates the receptor to signal.
Which pair has the strongest mitogenic signling?
HER2:HER3
Mitogenesis
The induction (triggering) of mitosis, typically via a mitogen.
Mitogen and mechanism of action
A mitogen is a peptide or small protein, that induces a cell to begin cell division: mitosis.
It triggers signal transduction pathways involving mitogen-activated protein kinase (MAPK), leading to mitosis.
Describe HER signalling pathway
Ligand binding causes a conformational change which leads to dimerisation.
Dimerisation activates the tyrosine kinase domain.
HER2 is in a conformation which promotes dimerisation.
Different combinations of receptors stimulate different signaling pathways.
HER pathways stimulate cell proliferation, survival and are anti-apoptopic.
Are HERs proto-oncogenes or tumor suppressor genes?
proto-oncogenes
How can HER become oncogenic?
Over expression
Mutation
What was published in 1984?
that a mutant form of HER2 (neu) promotes cancer in rats.
What is different about HER2 from the others and what can this lead to
HER2 doesn’t need a ligand – always in an active state, always ready to signal
why we get overexpression of protein and start to get cancer
Where is the HER2 gene frequently amplified?
in breast cancer samples