negative regulation of retinoic acid receptor signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of retinoic acid receptor signaling pathway activity. [GOC:dgh]

Negative regulation of retinoic acid receptor signaling pathway involves a complex interplay of molecular mechanisms that attenuate the activity of retinoic acid receptors (RARs), nuclear receptors responsible for mediating the effects of retinoic acid (RA). RA, a vitamin A derivative, plays a critical role in various developmental processes, including embryonic development, cell differentiation, and immune regulation. The signaling pathway is initiated by the binding of RA to RARs, which form heterodimers with retinoid X receptors (RXRs). These heterodimers bind to specific DNA sequences called retinoic acid response elements (RAREs) located in the promoter regions of target genes, leading to the regulation of gene expression. Negative regulation of this pathway is essential to prevent excessive activation and maintain homeostasis.

**Mechanisms of Negative Regulation:**

1. **Ligand Availability:**
* **RA synthesis and degradation:** The production and breakdown of RA are tightly controlled. Enzymes like retinaldehyde dehydrogenase (RALDH) are responsible for synthesizing RA, while cytochrome P450 enzymes like CYP26A1 and CYP26B1 catalyze RA degradation, limiting its availability.
* **RA sequestration:** Cellular proteins like cellular retinoic acid-binding protein (CRABP) bind to RA, reducing its availability for RARs.

2. **RAR expression and activity:**
* **RAR gene transcription:** The expression levels of RAR genes can be regulated by various factors, including other signaling pathways.
* **RAR phosphorylation:** Phosphorylation of RARs by kinases like protein kinase A (PKA) and protein kinase C (PKC) can modulate their activity and target gene selectivity.
* **RAR degradation:** Proteasomal degradation of RARs can reduce their levels in the cell.

3. **Corepressor Recruitment:**
* **Nuclear receptor corepressors (NCoRs):** In the absence of RA, RARs recruit NCoRs like NCoR1 and SMRT to the RAREs, leading to the repression of target gene transcription. NCoRs can act by recruiting histone deacetylases (HDACs), which remove acetyl groups from histones, causing chromatin condensation and silencing gene expression.

4. **Antagonist binding:**
* **RA antagonists:** Some compounds, like synthetic retinoic acid receptor antagonists, can bind to RARs and block the binding of RA, effectively inhibiting the signaling pathway.

5. **MicroRNAs (miRNAs):**
* **miRNA-mediated regulation:** Specific miRNAs can target RAR transcripts or downstream signaling proteins, regulating their expression and activity.

**Consequences of Negative Regulation:**

Negative regulation of RA signaling is crucial for:

* **Maintaining homeostasis:** Preventing excessive RA signaling, which could lead to developmental abnormalities and other pathological conditions.
* **Fine-tuning tissue-specific responses:** Ensuring appropriate levels of gene expression in different tissues and at different developmental stages.
* **Adaptive responses:** Allowing cells to adjust their responses to changing levels of RA or other environmental cues.

**Dysregulation and Disease:**

Disruption of the negative regulation of RA signaling can contribute to various diseases, including:

* **Cancer:** In some cancers, the expression of negative regulators of RA signaling is dysregulated, leading to aberrant RA signaling and tumor growth.
* **Developmental disorders:** Defects in RA signaling pathways can lead to birth defects and other developmental abnormalities.
* **Immune system disorders:** RA signaling plays a role in immune regulation, and dysregulation of this pathway can contribute to autoimmune diseases.

**Overall, negative regulation of RA signaling is a complex process involving multiple layers of molecular control. These mechanisms ensure that RA signaling is tightly regulated and functions appropriately in diverse physiological contexts. Disruptions in this pathway can have significant consequences for development and health.**"

Proteins (3)

Compounds (15)