Lecture 32 - ER Stress Response Flashcards
Protein kinases act sequentially in signalling cascades.
How is this beneficial?
Allows for the amplification of the signal.
Allows for diversification of the signal.
What are Chk1 & Chk2? How are they activated?
They are nuclear protein kinase in DNA response amplification.
Normally in a monomeric inactive form.
ATM autophosphorylates to activate itelf, then activates Chk2. Active Chk2 dimerises & reciprocally phosphorylate each other.
Chk1 is a downstream target of an ATM like protein called ATR, while Chk2 is a downstream target of ATM.
Cross talk occurs between the two pathways to ensure both are recruited. They mediate cell cycle arrest.
What is p53, and how is it activated?
It is an effector of the DNA damage response.
Chk2 phosphorylates it, which activates it by stabilising it.
It is normally in a complex with MDM2, directing it to the ubiquitination/proteosome pathway. It cannot bind if phosphorylated.
p53 also binds to the regulatory region of the p21 gene, which inhibits both Chk1 & Chk2 when expressed.
What is the problem with the ER, and how is it overcome?
It is very crowded in the ER, resulting in a high risk of protein aggregation.
In the adaptive response, an unfolded protein can be refolded or directed to an ubiquitination pathway for degredation (known as ERAD).
If both mechanisms fail, cell death is induced.
How can you induce an Unfolded Protein Response? What happens to counter it?
UPR can be induced by preventing glycosylation, disulphide bonds and chaperone actions.
During ER stress, chaperone capacity increases to promote correct folding/proteostasis.
Communication to the nucleus occurs via increased levels of transcription factors to aid in countering the stress.
Other processes that slow down translation are activated to reduce the load of the folding requirement.
What are the ER stress proteins, and what do they do?
ATFG - increase ER folding capacity only
PERK - increases ER folding capacity and decreases protein load
IREI - increases ER folding capacity and decreases protein load
Increasing ER folding capacity is a transcriptional response.
Decreasing protein load is a translational control response (mRNA decay)
What factor determines whether a cell tries to counter ER stress or induces cell death?
Time. If the cell cannot counter the ER stress quick enough, cell death will be induced after a certain amount of time. The cell cannot sustain ER stress for very long.
Fact
UPR response has been implicated in many metabolic, cancerous and neurodegenerative diseases.
