Stress response pathways
18 important questions on Stress response pathways
Is a TF transient or sustained?
Why do we study stress response pathways?
- Develop specific reporter assays for TF activation
- To understand mechanisms based on whole transcriptomic read outs
- Can help understand the molecular initiating events of toxicity
- Help predict outcomes based on these events
What are the effects of p53 activation? (3)
- Negative feedback of MDM2
- Cell cycle arrest -> interaction with cyclin dependent kinase. (↑ CDKN1A) p21 hierdoor gaat de cyclin dependent kinase inhibitor omhoog. ↑GADD45A -> blokkeert de kinase.
- Apoptosis -> Puma, BAX, BAK, FAS, PMAIP1, TP53AIP
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Where does it stop the cell cycle? And why?
- Cell cycle arrest in G1 or G2/M
- DNA repair and epigenetic regulation
What activates p53? One was already mentioned (7)
- ROS
- DNA damage
- Hypoxia
- Oncogene expression
- Ribosomal dysfunction
- Telomere attrition
- Nutrient deprivation
What are effects of p53 signals?
- Cell death -> apoptosis
- Cell cycle arrest
- DNA repair
- Senescence -> permantent peace
- Autophagy -> orderly degradation and recycling of cellular components
- Inhibits angiogenesis and migration => against tumors
- Inhibits metabolism => against tumors => SCO2 and TIGAR.
How much % of the cancers have a p53 mutation?
Name 4 examples that interact with the DNA and activate p53.
- Benzo(a)pyrene: Metabolite. DNA adduct. At Guanine.
- Cisplatin: Forms intrastrands, blocks DNA replication, triggers DNA damage response. At guanine.
- Aflatoxin: Metabolite. DNA adduct. Guanine
- Tamoxifen: weak interaction with DNA. Adducts.
Describe the pathway of Nrf2.
- Nrf2 is bind to Keap1 (2X)
The ubiqutine kinase is CUL3.
- Oxygen species (ROS) + electrofielen can release keap1 from nrf2.
- Nrf2 goes to the nucleus.
- In the nucleus it forms a heterodimer with s-MAF.
- Binding to ARE (Antioxidant Response Elements)/EpRE (electrofiel response elements) -> promotoren of antioxidant genes.
What does activate Nrf2?
Electrofiels
Which genes/pathways are activated by Nrf2? (3)
- Glutathione (antioxidant) metabolism and recycling: GCLC, GCLM (glutathion synthase), GSR (glutathion reductase/recycling)
- Xenobiotic metabolism and transport: GST (koppelt aan gluthation), ABCC3 (transporter)
- Reduction of oxygen species and quinones: HO-1 (hemeoxygenase), NQO1 (NAD(P)H Quinone Dehydrogenase 1), TXNRD1(reductase 1), SRXN1 (Sulfiredoxin-1)
Which molecules is important for keap1?
Cys151,Cys273, and Cys288, of KEAP1 are responsible primarily for the responses to a variety of electrophiles.
What is the relation between paracetamol and nrf2?
- Acetaminophen (paracetamol) can produce (when high dosissen) NAPQI.
- NAPQI: is an electrolite
- Bind to cysteine of the KEAP1.
What happens in a knockout nrf2 mice?
- They die when they are given a high dose of acetaminophen.
- High levels of ALT
- Decrease expression of ARE-regulated drug metabolizing enzymes and antioxidant genes.
What is the MTF pathway? Metal-responsive transcription factor.
- Zink is the activator.
- When there is oxidative stress, zink gets lost form the proteins
- Zink activates MTF-1.
- It goes to the nucleus.
- It forms a heterodimer.
- It binds to metal response element. MRE.
- Induction of pathays that remove heavy metals.
What are the target genes?
2. Zinc transporter SLC30A1, SLC30A2, SLC39A10
3. Others SEPW1, SELH, TXNRD2
So you need free metals. How does this occur?
Eating fish => methylmercury
One of the effects of MTF is the expression of metallothionein (MT). What is this and what does this? (5)
- Small protein
- Binds metal ions
- There are multipe types:MT1 (subtypes A, B, E, F, G, H, L, M, X), MT2, MT3, and MT4.
- Antioxidant
- important for homeostasis
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