20.3 Nuclear Receptors and Steroid Signaling
4 min read•august 9, 2024
Nuclear receptors are key players in steroid hormone signaling. These proteins act as ligand-activated transcription factors, binding hormones and regulating gene expression. Their modular structure allows for specific hormone and DNA interactions.
, derived from cholesterol, diffuse through cell membranes and bind to nuclear receptors. This binding triggers conformational changes, leading to receptor dimerization, DNA binding, and recruitment of coregulators, ultimately controlling gene expression in response to hormonal signals.
Nuclear Receptors and Steroid Hormones
Structure and Function of Nuclear Receptors
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- Nuclear receptors function as ligand-activated transcription factors
- Consist of modular protein domains with specific functions
- Ligand-binding domain (LBD) located at the C-terminal region interacts with specific hormones or ligands
- DNA-binding domain (DBD) situated in the central portion recognizes and binds to specific DNA sequences
- N-terminal domain contains a ligand-independent activation function
- Nuclear receptors can exist as monomers, homodimers, or heterodimers
Steroid Hormones and Their Signaling Pathways
- Steroid hormones derive from cholesterol and include estrogens, androgens, progestins, glucocorticoids, and mineralocorticoids
- Lipophilic nature allows steroid hormones to diffuse through cell membranes
- Bind to specific nuclear receptors in the cytoplasm or nucleus
- Hormone-receptor complexes translocate to the nucleus (if not already there)
- Complexes bind to specific DNA sequences called hormone response elements (HREs)
- Binding to HREs initiates transcriptional regulation of target genes
Mechanism of Nuclear Receptor Action
- induces conformational changes in the receptor
- Conformational changes lead to dissociation of heat shock proteins (HSPs) from the receptor
- Receptor dimerization occurs for many nuclear receptors
- DNA binding domain recognizes and binds to specific response elements in target gene promoters
- Recruitment of or corepressors modulates transcriptional activity
- Ligand-dependent activation results in either gene activation or
Transcriptional Regulation
Response Elements and DNA Recognition
- Response elements consist of specific DNA sequences recognized by nuclear receptors
- Often composed of two half-sites with a specific orientation and spacing
- Half-sites typically contain 6-base pair sequences
- Orientation can be direct repeats, inverted repeats, or everted repeats
- Spacing between half-sites varies depending on the specific nuclear receptor
- Examples include (EREs) and (GREs)
Coregulators in Nuclear Receptor Signaling
- Coactivators enhance transcriptional activity of nuclear receptors
- Coactivators include (SRC) family and (CBP)
- Coactivators often possess (HAT) activity to modify chromatin structure
- Corepressors suppress transcriptional activity of nuclear receptors
- Corepressors include (NCoR) and (SMRT)
- Corepressors often recruit (HDACs) to promote chromatin condensation
- Balance between coactivators and corepressors determines the overall transcriptional output
Transcriptional Regulation Mechanisms
- Ligand-dependent activation involves recruitment of coactivators upon ligand binding
- Ligand-independent activation can occur through phosphorylation of nuclear receptors
- Tethering mechanism allows nuclear receptors to regulate genes without direct DNA binding
- Cross-talk between nuclear receptor signaling and other signaling pathways (phosphorylation cascades)
- Negative regulation can occur through competition for DNA binding sites or coregulators
Specific Nuclear Receptors
Thyroid Hormone Receptor (TR)
- Binds T3 and T4
- Forms heterodimers with retinoid X receptor (RXR)
- Regulates genes involved in , growth, and development
- Unliganded TR acts as a transcriptional repressor
- Ligand binding induces conformational changes leading to corepressor release and coactivator recruitment
- Plays crucial roles in brain development, heart function, and energy homeostasis
Retinoic Acid Receptor (RAR)
- Binds retinoic acid, a derivative of vitamin A
- Forms heterodimers with RXR
- Regulates genes involved in cell differentiation, proliferation, and apoptosis
- Important for embryonic development and maintenance of epithelial tissues
- Three subtypes exist: RARα, RARβ, and RARγ
- Dysregulation of RAR signaling implicated in various cancers and developmental disorders
Estrogen Receptor (ER)
- Binds estrogens (estradiol, estrone, estriol)
- Exists as two subtypes: ERα and ERβ
- Regulates genes involved in reproductive function, bone metabolism, and cardiovascular health
- Can function through both genomic and non-genomic mechanisms
- Genomic actions involve direct binding to estrogen response elements (EREs)
- Non-genomic actions include rapid signaling through membrane-associated ERs
- Targeted by selective modulators (SERMs) for various therapeutic applications
Glucocorticoid Receptor (GR)
- Binds glucocorticoids ( in humans, corticosterone in rodents)
- Regulates genes involved in metabolism, , and stress adaptation
- Exists primarily in the cytoplasm when unliganded, complexed with heat shock proteins
- Ligand binding induces nuclear translocation and DNA binding
- Can both activate and repress gene expression depending on the cellular context
- Plays a crucial role in the body's stress response and anti-inflammatory actions
- Synthetic glucocorticoids (dexamethasone, prednisone) widely used as anti-inflammatory and immunosuppressive drugs
Key Terms to Review (28)
Cellular signaling pathways: Cellular signaling pathways are complex networks of interactions that allow cells to communicate with each other and respond to their environment. These pathways involve a series of molecular events triggered by various signals, such as hormones or growth factors, leading to specific cellular responses. In the context of nuclear receptors and steroid signaling, these pathways play a critical role in regulating gene expression and cellular functions, allowing for precise control over physiological processes.
Chromatin immunoprecipitation: Chromatin immunoprecipitation (ChIP) is a technique used to investigate the interactions between proteins and DNA in the context of chromatin. This method allows researchers to study how specific proteins, such as transcription factors or nuclear receptors, bind to particular regions of the genome, providing insight into gene regulation and the effects of steroid signaling pathways.
Coactivators: Coactivators are proteins that enhance the transcriptional activity of nuclear receptors and other transcription factors, playing a vital role in gene regulation. They interact with nuclear receptors in the presence of ligands, facilitating the recruitment of the transcription machinery and thus promoting gene expression. This process is essential for the proper functioning of steroid signaling pathways and influences various biological processes such as development, metabolism, and immune responses.
Cortisol: Cortisol is a steroid hormone produced by the adrenal glands that plays a vital role in regulating various physiological processes, including metabolism, immune response, and stress response. This hormone is crucial in helping the body respond to stress, maintain blood sugar levels, and control inflammation. Additionally, cortisol impacts lipid metabolism and influences nuclear receptors that modulate gene expression, linking it to a variety of metabolic pathways.
Creb-binding protein: CREB-binding protein (CBP) is a transcriptional coactivator that plays a crucial role in the regulation of gene expression by interacting with various transcription factors, including the cAMP response element-binding protein (CREB). CBP acts as a bridge between transcription factors and the transcriptional machinery, facilitating the recruitment of other proteins necessary for gene activation. This protein is particularly important in processes like cell signaling, differentiation, and memory formation in neurons.
Elwood Jensen: Elwood Jensen is a prominent American biochemist best known for his groundbreaking work on nuclear receptors and steroid hormone signaling. His research was pivotal in understanding how steroid hormones interact with their receptors inside cells, influencing gene expression and cellular responses. This work laid the foundation for the study of how hormones can act as signaling molecules to regulate various physiological processes in the body.
Estrogen receptor: The estrogen receptor is a type of nuclear receptor that binds to estrogen, a key hormone in the regulation of various biological processes, including reproduction, development, and metabolism. When estrogen binds to its receptor, it triggers a cascade of genetic and cellular responses that influence gene expression and cellular function, highlighting its critical role in steroid signaling pathways.
Estrogen Response Elements: Estrogen response elements (EREs) are specific DNA sequences located in the promoter regions of estrogen-regulated genes that play a crucial role in mediating the effects of estrogen on gene expression. These elements are recognized and bound by estrogen receptors, which are nuclear receptors activated by estrogen, leading to the initiation of transcription and the regulation of various biological processes such as growth, reproduction, and metabolism.
Gene expression regulation: Gene expression regulation refers to the various mechanisms that control the amount and timing of gene expression, ensuring that genes are turned on or off as needed. This process is crucial for maintaining cellular functions, development, and response to environmental changes. Different factors, including transcription factors, enhancers, and repressors, play significant roles in modulating gene expression at multiple levels.
Glucocorticoid receptor: The glucocorticoid receptor (GR) is a type of nuclear receptor that binds glucocorticoids, which are steroid hormones produced by the adrenal gland. When activated by these hormones, the GR translocates to the nucleus where it regulates the expression of specific genes involved in metabolism, immune response, and stress response, making it crucial for various physiological functions.
Glucocorticoid response elements: Glucocorticoid response elements (GREs) are specific DNA sequences found in the promoter regions of genes that mediate the actions of glucocorticoids, a class of steroid hormones. These elements play a critical role in gene expression by serving as binding sites for glucocorticoid receptors, leading to the regulation of various physiological processes such as metabolism, immune response, and stress responses.
Histone acetyltransferase: Histone acetyltransferase (HAT) is an enzyme that adds acetyl groups to the amino acids of histone proteins, leading to changes in chromatin structure and gene expression. This modification plays a crucial role in epigenetic regulation by influencing the accessibility of DNA to transcriptional machinery, making it easier for genes to be expressed. HATs are also involved in the signaling pathways related to nuclear receptors, which help regulate a variety of physiological processes.
Histone Deacetylases: Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues on histone proteins, leading to a more compact and transcriptionally inactive form of chromatin. By regulating the acetylation status of histones, HDACs play a crucial role in controlling gene expression and cellular processes, influencing both normal development and disease states.
Hormone-response element: A hormone-response element (HRE) is a specific DNA sequence located in the promoter region of a gene that serves as a binding site for hormone-receptor complexes. These elements play a crucial role in the regulation of gene expression by mediating the effects of steroid hormones, such as estrogen and testosterone, which can initiate transcription when bound to their respective receptors. The interaction between HREs and hormone-receptor complexes is a key step in the process of steroid signaling.
Immune response: The immune response is the body's defense mechanism against pathogens, such as bacteria and viruses, which involves a complex network of cells, tissues, and organs working together to identify and eliminate these foreign invaders. This response can be triggered by various signals, including the recognition of specific molecules on pathogens, and is crucial for maintaining health and preventing disease. The immune system operates through both innate and adaptive responses, where nuclear receptors play a significant role in regulating immune functions and steroid signaling can modulate inflammation and immune responses.
Ligand binding: Ligand binding refers to the interaction between a molecule, known as a ligand, and a specific target, such as a receptor or enzyme, resulting in a biological response. This process is crucial for the function of various signaling pathways and cellular responses, influencing how cells communicate and react to their environment. Ligand binding can activate or inhibit receptors, leading to a cascade of events that alter cellular functions.
Mary-Claire King: Mary-Claire King is a prominent American geneticist known for her groundbreaking research in human genetics and breast cancer. She is best recognized for her discovery of the BRCA1 gene, which is linked to hereditary breast and ovarian cancer, significantly influencing cancer research and genetic testing. Her work has advanced the understanding of how genetic factors contribute to cancer, particularly in the context of nuclear receptors and steroid signaling.
Metabolism: Metabolism refers to the sum of all chemical reactions that occur within a living organism to maintain life, including both the breakdown of molecules to obtain energy (catabolism) and the synthesis of all compounds needed for cellular processes (anabolism). This term is critical as it encompasses how organisms convert food into energy and how this energy is utilized for various biological functions, while also linking it to hormonal regulation and cellular signaling pathways.
Nuclear Receptor Corepressor: A nuclear receptor corepressor is a protein that inhibits the transcriptional activity of nuclear receptors, which are proteins that mediate the effects of steroid hormones and other signaling molecules by binding to DNA and regulating gene expression. These corepressors are essential for maintaining the balance of gene expression, as they help to silence genes when specific ligands are not present, thereby playing a critical role in steroid signaling pathways and the overall regulation of cellular functions.
Reporter assays: Reporter assays are experimental techniques used to measure gene expression or activity by utilizing a reporter gene, which produces a measurable signal, such as fluorescence or luminescence. These assays are crucial in studying nuclear receptors and steroid signaling, as they allow researchers to assess how these receptors regulate target genes in response to various stimuli, such as hormones or other signaling molecules.
Repression: Repression is a regulatory mechanism that inhibits the expression of specific genes, thus controlling the production of proteins within a cell. This biological process is crucial for maintaining cellular homeostasis and responding to environmental signals, particularly in the context of nuclear receptors and steroid signaling, where it modulates gene expression in response to hormones and other signaling molecules.
Silencing Mediator for Retinoid and Thyroid Hormone Receptors: The silencing mediator for retinoid and thyroid hormone receptors is a complex of proteins that play a crucial role in the regulation of gene expression by modulating the activity of nuclear hormone receptors. This mediator interacts with both retinoid receptors and thyroid hormone receptors, helping to repress transcription when these receptors are not activated by their respective ligands. By doing so, it ensures that genes are expressed only under specific physiological conditions, maintaining cellular homeostasis.
Steroid hormones: Steroid hormones are a class of hormones derived from cholesterol that play critical roles in regulating various physiological processes in the body. These hormones are lipophilic, allowing them to easily pass through cell membranes and bind to intracellular receptors, which then influence gene expression and cellular function. Their structure, characterized by a four-ring carbon skeleton, classifies them as steroids and connects them to key biological functions such as metabolism, immune response, and development.
Steroid receptor coactivator: A steroid receptor coactivator is a protein that enhances the transcriptional activity of nuclear hormone receptors, particularly steroid hormone receptors. These coactivators play a critical role in mediating the effects of steroid hormones by facilitating the recruitment of additional proteins necessary for gene expression, ultimately influencing various physiological processes such as metabolism, development, and reproduction.
Testosterone: Testosterone is a steroid hormone primarily produced in the testes in males and ovaries in females, known for its key role in the development of male reproductive tissues and secondary sexual characteristics. This hormone belongs to the androgen group and is vital for various biological processes, including muscle growth, bone density, and the regulation of libido. It also interacts with nuclear receptors to elicit gene expression changes, highlighting its significance in cellular signaling.
Thyroid hormones: Thyroid hormones are biologically active molecules produced by the thyroid gland, primarily thyroxine (T4) and triiodothyronine (T3). These hormones play crucial roles in regulating metabolism, growth, and development in the body. They influence various physiological processes, including energy expenditure, protein synthesis, and the metabolism of carbohydrates and fats.
Transactivation: Transactivation is the process by which a nuclear receptor, upon binding to its ligand, activates the transcription of specific target genes by recruiting coactivators and other transcriptional machinery. This mechanism plays a crucial role in cellular signaling, particularly in the context of steroid hormones, where the nuclear receptors function as transcription factors to mediate gene expression changes that influence various physiological processes.
Transcriptional activation: Transcriptional activation is the process by which gene expression is increased, leading to the synthesis of RNA from a DNA template. This involves the recruitment of transcription factors and coactivators to specific promoter regions, enhancing the assembly of the transcriptional machinery and promoting RNA polymerase activity. The regulation of transcriptional activation is critical for cellular responses and plays a key role in various biological processes, including development, differentiation, and response to environmental signals.