Nuclear receptor TF + hormone regulators

What is meant by Intracellular gene regulation by Transcription Factors?

Small lipophilic molecules diffuse across the plasma membrane and interact with intracellular receptors e.g. nuclear hormone receptors.

What is meant by Extracellular gene regulation by Transcription Factors?

• Hydrophilic - eg. peptide hormones such as insulin, growth factors, and glucagon

• Lipophilic molecules that bind to cell-surface receptors – prostaglandins

What are some examples of the Nuclear Receptor Superfamily of Transcription factors?

Examples include steroid hormone receptors e.g. estrogen, thyroid hormone receptors, and retinoic acid receptors.

What is the difference between nuclear and cytoplasmic nuclear receptors?

• Homodimers can be nuclear AND cytoplasmic e.g. GR & activity is regulated by controlling transport from cytoplasm → nucleus

• Heterodimers are exclusively nuclear Heterodimers, e.g. RXR-TR, controlled by absence/ presence of hormone ligand, which induces a conformational change that facilitates binding to specific DNA regions and gene regulation.

What is an example of gene regulation by Homodimeric Nuclear Receptors?

e.g Glucocorticoid Receptor

Absence of Hormone:

• GR anchored in cytoplasm complexed to inhibitor complex through LBD (ligand binding domain)/ Hormone BD.

Presence of Hormone:

• Conformational change in GR and is released from cytoplasmic anchor and enters nucleus

• Binds target gene response elements

• Activates transcription by histone acetylation and facilitating co-operative assembly of transcription initiation complex

What is the significance of palindromes to the binding of receptors to the HRE (hormone response elements)?

Palindromic sequences in hormone response elements (HREs) facilitate receptor dimerisation, enhancing the specificity and stability of transcription factor binding to DNA.

The ability of binding to these different motifs implies that the DBDs can rotate with respect to the LBDs that are held together through the dimerization interface

How can the Vitamin D Receptor (VDR) have possible homo and heterodimer interactions with other receptor members of the superfamily?

VDR can form both homodimers and heterodimers with other nuclear receptors as it is composed of 2 ZF motifs, with each dimer pair having an enhanced affinity for distinct DNA targets allowing a small family of receptors to generate a diverse range of physiological effects.

It interacts with partners, such as RXR, RAR, T3R

What is the biologically active form of Vit D?

1α,25(OH)2 vitamin D3 [1α,25(OH)₂ D3] (1,25-Dihydroxyvitamin D) functions as a steroid hormone

How does the steroid hormone 1,25-Dihydroxyvitamin D interact with the VDR and regulate genes regulated by Vit D?

• VDR is a ligand controlled TF, (RXR Heterodimer)

• Formation of VDR-RXR heterodimers bind to Vit D responsive elements (VDREs) on DNA

• Induction of rapid changes in tissue-specific expression of VitD-regulated genes

The key organ in the vitamin D endocrine system is the kidney where the hormonal 1α,25(OH)2 D3 is produced and circulates in the blood

➢ Liganded VDR–RXR functions in osteoblasts/osteocytes function