Nuclear receptors Flashcards
What are nuclear receptors?
Ligand dependent transcription factors that play a key role in gene expression.
What is a common example of nuclear receptors?
Steroid receptors, which are involved in breast and prostate cancer treatment.
What is the structure of nuclear receptors?
They consist of a DNA binding domain (DBD) and a ligand binding domain.
What is the function of the DNA binding domain (DBD)?
It reads the DNA and binds to hormone response elements (HRE) on DNA.
What are zinc fingers?
Structural motifs on the DBD or HRE that facilitate binding.
What happens upon ligand binding in nuclear receptors?
It induces co-activator recruitment and transcriptional activation.
What is the role of helix 12 in nuclear receptors?
In absence of agonist, helix 12 interacts with co-repressors; in presence of agonist, it changes orientation to become accessible to co-activators.
What are the functions of nuclear receptors?
They play a key role in receptor dimerization and ligand dependent transactivation.
What do Type 1 steroid receptor agonists induce?
Heat stress protein (HSP) dissociation, nuclear translocation, receptor dimerization, and transcription activation.
What do Type 2/3 heterodimeric receptor agonists induce?
Corepressor dissociation and coactivator recruitment.
What is the role of corepressors in the absence of agonists?
They switch off transcription, leading to active repression.
What is the effect of ATRA on nuclear receptors?
In absence of ATRA, NRs recruit corepressors and repress transcription; in presence, they recruit co-activators and activate transcription.
What are some examples of co-activators?
Steroid receptor co-activators (SRC 1/2/3), histone acetyl transferases, and p300/CBP.
What is the histone code hypothesis?
Transcription is regulated by modifications to histone proteins.
What is the role of histone acetylation?
It decreases the positive charge of histones, making DNA more accessible for transcription.
What are the classes of histone deacetylases (HDACs)?
Class 1, Class 2, Class 3, and Class 4, each with unique roles in transcription regulation.
What is the function of lysine methyltransferases (KMTs)?
They add methyl groups to lysine residues on histones, influencing transcription.
What is the significance of co-regulators in nuclear receptor function?
They can be covalently modified, affecting the transactivational output of NR regulated transcription.
What is the role of the mediator complex?
It helps in the recruitment of RNA polymerase II and transcription factors to activate transcription.
What happens during histone demethylation?
Cells have developed mechanisms to demethylate histones, affecting transcription regulation.
What is the function of LSD1?
It demethylates H3K4 and associates with repressive complexes, influencing transcription.
What is the role of p300 and CBP?
They act as scaffolds to recruit other proteins and enhance transactivation of multiple classes of transcription factors.
What does SRA stand for?
Steroid receptor RNA activator 1
What type of RNA is SRA?
Type of lncRNA
What are the co-activator functions of SRA?
Enhance AF-1, the ligand independent transactivation of steroid type 1 and 2 NRs
What is noted about SRA splice variants?
SRA splice variants detected in tumour cell lines
How many isoforms of SRA are there?
Several isoforms
What does some SRA isoforms encode?
Endogenous protein (SRAP)
What is the function of some SRA isoforms?
Unclear function
What role do long non-coding RNAs (lncRNAs) play?
LncRNA promotes NR-transactivation
What could be a therapeutic goal regarding lncRNAs?
Reduce production of lncRNAs instead of targeting co-regulators
What are some clinical consequences of co-regulator disruption?
Carcinogenesis, epigenetic silencing of tumour suppressor genes, cancer cell proliferation
What is the effect of overexpression of SRC-3/AIB1 in breast cancer?
May potentiate growth enhancing actions of oestrogens on breast cancer cells
What is essential for prostate cancer development?
Androgen receptor
What does the PML-RARa fusion oncoprotein do?
Inappropriately recruits co-repressors
What can coactivator defects lead to?
Numerous hormone resistance syndromes
What are examples of hormone resistance syndromes?
Androgen insensitivity, thyroid hormone resistance
What is associated with type 2 diabetes?
?PGC1 coactivator family
What mutation is found in insulin resistance, diabetes, and hypertension?
PPARy helix12 mutation
What is Tamoxifen classified as?
SERM (selective modulator)
What is the action of Tamoxifen in different tissues?
Acts as ERa antagonist in mammary tissue, but ERa agonist in uterine tissue
What is the effect of blocking Myc and IGF in breast tissue?
Drives cancer growth in MCF-7 line but not in Ishikawa cell line
What difference is noted in SRC1 levels?
Difference in SRC1 levels between breast and uterine tissue
What happens with overexpression of SRC1?
Tamoxifen becomes agonist not antagonist
What can SRC-1 overexpression in breast tissue lead to?
Resistance to tamoxifen and is an independent risk factor for breast cancer recurrence
