Boster Pathways-> Epigenetics

Nuclear Receptor Signaling Pathway

an Overview of Nuclear Receptor Signaling Pathway

The nuclear receptor superfamily comprises transcription factors that are activated by ligands and play a variety of roles in cell differentiation/development, proliferation, and metabolism. They are associated with a variety of pathologies, including cancer, cardiovascular disease, inflammation, and reproductive abnormalities. Members of this family have an N-terminal transactivation domain, a highly conserved zinc-finger DNA-binding domain in the central region, and a C-terminal ligand-binding domain. When a ligand binds to its corresponding nuclear receptor, specific genes within a target tissue are transactivated.

Many and different people were involved in different discoveries regarding chromatin and its remodeling . Some include (Walter Fleming) who discovered chromatin in 1880,(John,E.W) who discovered The histones, Their interactions with DNA and some aspects of gene control in 1969,(wolffe, A) who discovered chromatin structures and its functions.

Mechanism of Action

Apart from ligand binding, nuclear receptor activity can be modulated by a variety of growth factor and cytokine signaling cascades that result in the phosphorylation or other post-translational modifications of the receptor, typically within the N-terminal transactivation domain. For instance, the estrogen receptor is phosphorylated on a number of serine residues, which affects the receptor's activity. Ser118 may be a CDK7 substrate, whereas Ser167 may be phosphorylated by p90RSK and Akt. Phosphorylation of Ser167 in breast cancer patients may confer resistance to tamoxifen. The estrogen receptor, androgen receptor, progesterone receptor, mineralocorticoid receptor, and glucocorticoid receptor are all examples of type I nuclear receptors. Steroid hormone ligands for this subgroup of receptors travel through the bloodstream bound to steroid binding globulin from their respective endocrine gland. Certain type I nuclear receptors are activated in part when their cognate ligand is bound in the cytoplasmic compartment. The ligand-receptor complex dissociates from HSP90 and enters the nucleus, where it homodimerizes and binds to hormone response elements located within a target gene's promoter. The transactivation domain of the receptor is responsible for interacting with coactivators such as acetyltransferases and the general transcription machinery at the promoter, resulting in transcriptional activation.

Thyroid hormone receptors (TR and ), retinoic acid receptors (RAR, and ), vitamin D receptors (VDR), and peroxisome proliferator-activated receptors (PPAR, and ) are all examples of type II nonsteroid nuclear receptors. This family's members form heterodimers with the retinoid X receptor (RXR). Prior to ligand binding, receptor heterodimers are found in the nucleus as a component of complexes with histone deacetylases (HDACs) and other co-repressors that maintain target DNA in a tightly wound conformation, preventing it from being exposed to transacting factors. Ligand binding results in the dissociation of co-repressors, the derepression of chromatin, and transcriptional activation.

Orphan nuclear receptors are nuclear receptors with unidentified endogenous ligands. According to structural studies, some orphan receptors may be unable to bind ligands. This class of nuclear receptors includes the small heterodimer partner (SHP), reverse orientation c-ErbA (Rev-Erb and ), testicular receptors 2 and 4 (TR2 and 4), tailless homolog orphan receptor (TLX), photoreceptor-specific nuclear receptor (PNR), chicken ovalbumin upstream promoter transcription factor 1 and 2 (COUP-TF1 and 2), Nur77, Nur-related protein 1 (NURR1), neuron derived or (GCNF). The majority of these receptors regulate transcription by binding monomers or homodimers to their target DNA elements and recruiting chromatin-modifying coactivators and the transcription machinery.

Nur77 and NURR1 can also heterodimerize with RXRs, and these heterodimers can regulate transcription in response to RXR ligands.