Transcription & Inflammation Flashcards
(15 cards)
Nuclear factor kappa - 5
- Nuclear factor of kappa: A transcription factor associated with activation of inflammatory genes.
- Contains conserved sequences known as the Rel domain
- Inhibited by IkB, which binds across the Rel domain, dampening the inflammatory response.
- The pathway is triggered by stress upon cells,
e.g. infections, UV radiation, cytokines, IL-1 - NFkB major inducer of asthma & COPD related inflammation, & overexpression/activation implicated in many cancers.
Activator Protein - 1 - 3
Activator Protein - 1
1. Regulates immediate early response genes, & several cell functions e.g. cell growth.
2. Comprises a dimer of Fos & Jun families.
3. Requires transcription of Fos family member & phosphorylation of Jun family member.
Cellular function transcriptionally controlled - 4
- Process controlled to prevent aberrant proliferation.
- Cell signalled to proliferate through growth factors binding to receptors.
- Activation of intracellular signalling pathways leads to gene transcription.
- Results in expression of proteins required to drive the cell through the cell cycle.
Molecular basis of the cell cycle - 4
- Driven by two protein families
- Cyclins (transcription dependent)
- Cyclin-dependent kinases (activation dependent)
- Phosphorylation by CDKs key in controlling cell cycle.
Cell cycle initiation - 5
- G1 is the first stage of the cell cycle.
- Growth factor is stimulated, allowing transcription of c-Fos & phosphorylation of c-Jun.
- Transcription of cyclin D raises cyclin D1 levels
- Cyclin D/CDK4 complexes arise to phosphorylate pRb.
- pRb releases & activate E2F, so cyclin E can be transcribed, allowing G1 to move into the S-phase
What two groups of CDK inhibitors are there & how do they work - 3
2 groups of CDK inhibitors:
INK4 - inhibits CDK4/6
CIP/Kip inhibits all CDKs
- Transcriptionally regulated.
- Bind to cyclin/CDK complexes to prevent activation so that the cell cycle is inhibited - supressing growth.
- Balance between cyclin/CDKs & CKIs is important.
Endogenous corticoids - 3
- Released from the adrenal glands.
- Mineralocorticoids - aldosterone
+ Affect water & electrolyte balance. - Glucocorticoids - hydrocortisone & corticosterone
+ affect carbohydrate & protein metabolism also anti-inflammatory & immunosuppressive effects.
HPAA Axis - 2
- The hypothalamus, pituitary & adrenal.
- Circulation of signal to the adrenal gland that dictates whether to release & how much of steroids to release.
Factors influencing steroid release - 3
- Circadian rhythm
- Stresses can trigger fluctuations in hypothalamus’ release of corticotropic hormones that act on the pituitary gland to release ACTH, which acts on the adrenal gland to initiate hormone release.
- Under stress cortisol levels are higher in the body.
Why do we wean off steroids?
Adrenal crisis and inflammatory rebound can occur.
Cushing’s syndrome metabolic S/Es - 3
- Osteoporosis: thinning of bone structure, steroids decrease collagen synthesis so decreases osteoblast & Ca2+, due to inhibition of Vitamin D.
- Diabetogenic due to decrease in glucose uptake & utilisation, & increase in gluconeogenesis & appetite. Can result in obesity.
- Mineralocorticoid effects also cause: Na+/H2O retention, hypertension, oedema & CV events.
steroids act as transcription factors - 3
- Lipophilic hormones can diffuse through plasma membrane, allowing them to bind to intracellular receptors to translocate into the nucleus.
- Bind as homo(GR) & hetero(Vit D) dimers.
- Allows them to act as transcriptional activators & suppressors, so they can execute long term effects - may take weeks to maximise effects.
MoA of glucocorticoids - 2 & 3 options
- Enter cells & bind to the cytoplasmic receptors
- The complex translocates to the nucleus to act as transcription factor. This can:
Bind to response elements & activate anti-inflammatory gene transcription
Bind & repress pro-inflammatory gene activation
Interact & inhibit binding of other transcription factors
Stress’ effect upon Nuclear factor kappa B - 3
- Activates the signalling pathway (IkB kinases)
- IkB kinases phosphorylate the IkB to expose the Rel domain
- Allows NFkB to bind & conduct gene transcription.
Main functions of AP-1 - 4
- Regulates many genes involved in cell growth & differentiation
- Role in bone development (+VDR)
- Implicated in inflammation (+NFkB)
- May have a role in long term memory (+CREB)
