Endocrine Signalling 2 Flashcards
What is the hormone response element
The region of DNA the hormone binds to (promoter usually)
What can the sequence of the HRE determine
Whether the receptor will activate or repress transcription of the neighbouring promoter
What are the classes of hormone response elements and their sequences
Class I - AGAACA repeats
All others - AGGTCA repeats
What receptors activate class 1 HRE
Androgen receptor
Glucocorticod receptor
Mineralcorticod receptor
Progesterone receptor
What are class two HREs specific for
Oestrogen receptor
What are class III HREs specific for
Use AGGTCA but different receptors bind depending on the number of spaces (random bases) between two AGGTCA sequences
Provides specificity
What are class IV HREs specific for
Bind as monomers to nerve growth factor 1B and REv-erb (orphan receptor)
How do these DNA binding domains bind to HRE sites
Split into two halves -
One will have a high affinity for its HRE
One will not match up with HRE so low affinity.
When the high-affinity one binds, the poor affinity site changes shape (due to hinge etc) and this makes it complementary to the other HRE.
Causes a double bind
Why are there two HRE sites per binding
Because most nuclear receptors pair up and bind as dimers
What role do cofactors have regarding AF1 and AF2
Form a bridge between them
What do basal transcription factors bind to
The basal transcription factors bind to a set of core elements in a promoter (TATA box, Initiator element (Inr) and downstream promoter element (DPE)
How do nuclear receptors work in transcribing
The binding of nuclear receptors to an HRE (enhancer) stimulates the assembly of a stable basal factor/RNA pol II transcription PIC at the promoter.
Via chromatin
How do nuclear receptors form a stable PIC (2 processes)
Help PIC assembly by making direct contact with components of the basal transcription machinery
Recruits coactivators that promote PIC assembly through direct contact with components.
How does the action on chromatin by DNA receptors work to initiate transcription
Covalent modification of lysine, arginine and serine residues occurs and the histone N-terminal tails can change properties which opens up the chromatin by acting on the histones (co-factors directly)
How do these co-factors governed by the DNA receptors open the chromatin
Enzymatic activity to post-translatory modification of the histone which opens up the DNA
This can be reversible by the receptors bringing in repressive co-factors to tightly bind the DNA again
How is the shutting off of DNA binding and transcription done
Chaperone protein (P23 and hsp90) can promote the removal of nuclear receptors and RNA pol II from DNA potentially to be ready again to receive a signal.
If need them again quickly - keep nuclear receptors in the nucleus
If don’t need them again quickly - remove them from the nucleus
What is the difference between gene repression and shutting off the gene by nuclear receptors
Gene repression binds to the gene to prevent ANY activity from happening
Gene shut off stops transcription but allows other binding to take place if needed
What hormones are good at gene repression
Steroid hormones stay bound to the DNA -
With ligand-activation
Without ligand - repression (as allows nothing else to bind)
How does nuclear receptor gene repression occur
No ligand is bound to the nuclear receptor which changes its shape.
It recruits corepressors which inhibits the binding of the PIC and RNA polymerase via methylation usually
How do anti-hormones act and what is their role
Anti-hormones, important for pharmaceutical agents.
It works by entering the cell as hydrophobic, it then binds to the nuclear receptor which causes a different shape change which causes it to recruit co-repressors.
What is the negative response element and how does it work
In the absence of hormone to these elements, it activates transcription and in the presence of the hormone in these elements, it represses transcription.
It does this through the DNA repeats - changes from serious when bound to in parallel.
What is repression and cross-talk between pathways and how does it work
Method of nuclear receptors working without binding to hormone response elements.
Fos and Jun (regulate the expression of a myriad of genes in a variety of tissues and cell types) are phosphorylated by JNK and inhibited by nuclear receptors such as thyroid and glucocorticoid receptors.
Glucocorticoid receptors can inhibit NF-kappaB (an important inflammatory mediator)
Thyroid hormone receptors bind to cAMP which is important for gene transcription.
How is endocrine signalling important in myeloid progenitor cells
A retinoic acid receptor is required for myeloid cell differentiation.
If no ligand is present, the retinoic acid receptor is repressed - increasing myeloid progenitor cell proliferation increases.
When retinoic acid is bound to its nuclear receptor, the myeloid progenitor cell proliferation stops and differentiation of these cells occur
What happens to the endocrine signalling pathway of retinoic acid in acute promyelocytic leukaemia
Chromosomal translocation mutation causes a new hybrid gene (part retinoic acid receptor and part PML gene) - still works as a transcription factor but proliferation continues causing leukaemia
