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12.11: Signaling by Steroid Hormones

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    15119
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    Introduction

    We will now consider signaling by steroid hormones. These hormones are derivatives of cholesterol, which is found in membrane bilayers and lipoproteins. They are mostly nonpolar. Steroid hormones can affect signaling in two major ways:

    • through binding to membrane receptors, which when occupied effect signaling through the myriad of ways we discussed throughout this chapter. These effect would be rapid.
    • through bind to cytoplasmic receptors after they diffuse into the cell through passive and active means. This signaling is hence similar to retrograde signaling by nitric oxide, which can passively diffuse out of a cell and enter and adjacent cell to effect signaling in that cell. If the steroid primary messenger is in the cell, it most often can enter the nucleus and regulate gene transcription. Binding to cytoplasmic receptors account for most of the biological effects of steroid hormones. Since transcription is involved, the pathways elicit a slower response.

    We will briefly discuss the first type of signaling (binding to membrane receptor) mostly by presenting figure which describe their signaling pathways. Then, we will focus on steroid hormone activation of gene transcription.

    There are many classes of steroid hormones. These are illustrated in Figure \(\PageIndex{1}\) below along with their overall synthetic pathway.

    Steroidogenesis.svg

    Figure \(\PageIndex{1}\): Diagram of the pathways of human steroidogenesis. WikiJournal of Medicine 1 (1). DOI:10.15347/wjm/2014.005. ISSN 20018762.

    The overall families include progestagens and estrogens (female sex hormones), androgens (male sex hormones), glucocorticoids (like cortisol which affects immune and metabolic systems) and mineral corticoids (affect salt/water balance).

    We will mostly use the estrogens in the section as a prototypical examples and because their involvement in breast cancer and epidermal growth factor receptors.

    Steroid hormone signaling through binding to membrane receptors

    Most of this subsection is taken from and adapted fro the following source:

    Most people think of steroid signaling, it is through their nuclear effects on gene transcription (the predominant signaling effect). Signaling at the cell membrane is an emerging area of interest. We will present steroid signaling at the cell nucleus in four figures with their associated captions. We present these lesser known effects of steroid signaling first, since they utilize many of the pathways we have already studied. The figures will also give you a short review of some canonical pathways, which is always good in a field so complicated as signal transduction. The figures focus on signaling effect in cancer.

    Figure \(\PageIndex{2}\) shown membrane signaling through androgen receptors.

    Molecular Characterization of Membrane Steroid Receptors_Fig1AndrogensAI-01.svg
    Figure \(\PageIndex{2}\): Membrane androgen receptor-associated pathways and their effect on hormone-sensitive cancer progression (breast cancer as BC, prostate cancer as PC). Receptors are: ZIP9 (Zinc transporter), OXER1 (Oxoeicosanoid receptor 1), TRPM8 (Transient receptor potential cation channel subfamily M member 8), CAV1.3 (Voltage-dependent L-type calcium channel subunit alpha-1C). Masi et al. Cells 2021, 10(11), 2999; https://doi.org/10.3390/cells10112999. Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

    Figure \(\PageIndex{3}\) below shows membrane signaling through estrogen receptors

    Molecular Characterization of Membrane Steroid ReceptorsFig3Estrogen.svg
    Figure \(\PageIndex{3}\): membrane estrogen receptor-associated pathways and their effect on hormone-sensitive cancer progression (breast cancer as BC, prostate cancer as PC, endometrial cancer as EC, ovarian cancer as OC and testicular germ cell cancer as TGCC). Other abbreviations: multi-drug resistance (MDR), anchorage-independent growth (AIG). Receptors are GPER (G-protein coupled estrogen receptor), NaV1.2 (Sodium channel protein type 2 subunit alpha). Masi et al. Ibid

    A tamoxifen (a selective estrogen receptor modulator used in breast cancer therapy) binding site has been found in NavMs voltage-gated sodium channels.

    Figure \(\PageIndex{4}\) show membrane signaling through membrane progesterone receptors

    Molecular Characterization of Membrane Steroid ReceptorsProgestinsAI-01.svg
    Figure \(\PageIndex{4}\): Membrane progesterone receptor-associated pathways and their effect on hormone-sensitive cancer progression (breast cancer as BC, prostate cancer as PC, ovarian cancer as OC, and basal phenotype breast cancer as BPBC). Receptors are mPR (Membrane progestin receptor). Masi et al. ibid

    Figure \(\PageIndex{5}\) shows membrane associated progesterone receptors effects from progesterones signaling.

    Molecular Characterization of Membrane Steroid ReceptorsFig4ProgestingMAPK-01.svg
    Figure \(\PageIndex{5}\): MAPK associated pathways breast cancer as BC, endometrial cancer as EC, ovarian cancer as OC, Leydig cell tumor as LCT and cervical cancer as CC). Other abbreviations: anchorage-independent growth (AIG). Receptors are PGRMV (Membrane-associated progesterone receptor component 1), GIG47 (Neudesin). Masi et al. ibid.

    Steroid hormone signaling through binding to cytoplasmic receptors and activation of gene transcription

    Now we will explore the major effects of steroid hormones on signaling, in which steroids enter the cell, binding to cytoplasmic receptors, and then translocate into the nucleus where they regulate gene expression. The naming of steroid receptors can be confusing since it is important to differentiate steroid receptors that are resident in the cell membrane and those that move to the nucleus. An added complexity arise from the factor that some nuclear receptors can be covalently modified with a fatty acid (palmitoylated) and targeted to the cell membrane. Estrogen receptors target to the membrane can then act independent of their nuclear transcriptional activity.

    We will primarily focus steroid hormone effects in breast cancer (most diagnosed cancer) that are mediated through the nuclear steroid receptors, which belong to the nuclear receptor superfamily. Tamoxifen, a commonly used drug in the treatment of breast cancer is estrogen receptor antagonist (also called an estrogen receptor modulator—SERM).

    Molecular Function of Steroid Receptors—Common Features

    Steroid receptors (SR) consist of four main domains, the C-terminal ligand-binding domain (LBD), the DNA-binding domain (DBD), the hinge region and amino-terminal domain (NTD). Each SR contains also two motifs called activation function 1 and 2 (AF1 and AF2) within NTD and LBD, respectively, and are crucial for regulation of gene transcription. Two zinc fingers are located in the DBD. Figure \(\PageIndex{6}\):

    SteroidReceptorsBreastCancerFig2.svg
    Figure \(\PageIndex{6}\): Schematic illustration of steroid receptor structure. NTD—amino-terminal domain, DBD—DNA-binding domain, H—hinge region, LBD—ligand-binding domain, AF1—activation function 1, AF2—activation function 2. The diagram does not show the exact length proportion of the domains because it differs between distinct SRs. Kowalczyk, W.; Waliszczak, G.; Jach, R.; Dulińska-Litewka, J. Steroid Receptors in Breast Cancer: Understanding of Molecular Function as a Basis for Effective Therapy Development. Cancers 2021, 13, 4779. https://doi.org/10.3390/cancers13194779. Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

    The domains are often labeled A-F. The N-terminal domain (NTD) is also called the A/B domain. It can also bind DNA and can weakly activate transcription in the absence of hormone. The C domains is the DNA binding domain (DBD) contaning Zn fingers, which bind to the steroid response element in promoters of key genes.. The D domain is the hinge domain, and The E domain binds hormone (like estrogen) and protein regulators and when bound can activate gene transcription. The last domain (F) varies in length and its function is not completely clear.

    The specific DNA structure for the estrogen receptor from Pfam is shown in Figure \(\PageIndex{7}\) below.

    estrogenreceptrodomain.png
    Figure \(\PageIndex{7}\): Estrogen receptor domain structure.

    The green is the N-terminal Oest_recep domain (NTD, A/B). The red zf-C4 is the DNA binding domain which has two Zn fingers that bind DNA (DBD, C). The blue Hormone_Receptor is the ligand (estrogen) binding domain (LBD, domain E). The yellow is the C-terminal domain (F).

    There two genes for the estrogen receptor encoding ERα and ERβ. The transcriptionally active form is a dimer which forms on binding of estrogens. The dimer than translocates to the nucleus and activates transcription at ERE sites. The ERα dimer promotes estrogen-dependent growth while the ERβ dimer inhibits it. Heterodimers can form which seem to reduce the proliferative effects of ERα. Both ERα and ERβ can be expressed in

    Figure \(\PageIndex{8}\) below shows an interactive iCn3D model of the human estrogen receptor computational model (P03372, AlphaFold)

    Full human estrogen receptor computational model (P03372- AlphaFold).png
    Figure \(\PageIndex{8}\): Full human estrogen receptor computational model (P03372, AlphaFold) (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...XAk1jUHred87c9
    • red spacefill: Nterminal Met
    • green backbone trace: N-terminal domain disordered, which can bind DNA
    • magenta backbone trace: DNA binding domain with Zn fingers. Cys side chains of the Zn fingers are shownin sticks, cpk colors, and labeled.
    • blue: Hormone_Receptor is the ligand (estrogen) binding domain (LBD, domain E)
    • yellow: C-terminal tail (domain)
    • Cyan spacefill: C terminal Val

    There are no full length crystal structures of ER dimer. Most available structures are for the estrogen binding domain. It's really useful to see the full predicted structure to see how all the domains are connected, but perhaps more interestingly, the extended regions of disordered structures ,which you should imagine adopting specific structures on interaction with key signaling partners.

    Figure \(\PageIndex{9}\) below shows an interactive iCn3D model of the ligand binding domain of human estrogen receptor ERα bound to the antagonist tamoxifen (3ERT).

    Ligand binding domain Hu estrogen receptor- tamoxifen (3ERT)V2.png
    Figure \(\PageIndex{9}\): Ligand binding domain of human estrogen receptor ERα bound to the antagonist tamoxifen (3ERT) (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/icn3d/share.html?hhKXF19sVHS5RPys9

    The ligand binding domains (one for each of the ERα monomers) are shown in magenta and cyan. The antagonist Taxmoxifen, one bound in each of the ligand binding domains, is shown in sticks, CPK color. The amino acids comprising the binding site for tamoxifen, are shown in stick, CPK colors and labeled in the magenta subunit. The CPK colored spheres show the binding site on the ligand binding domain for other binding proteins called corepressor or coactivator (not shown, discussed below).

    Figure \(\PageIndex{10}\) below shows the structures of estrogens and selective estrogen receptor modulators (SERMs).

    Breast-related_effects_of_selective_estrogen_recepFig1.svg
    Figure \(\PageIndex{10}\): Structures of estrogens and selective estrogen receptor modulators (SERMs). Smith et al. Breast Cancer Research. 2014, 16:212. http://breast-cancer-research.com/content/16/3/212. CC BY 2.0

    The iCn3D model for the human estrogen receptor ERα bound to the antagonist tamoxifen (3ERT) showed binding sites for other proteins called coactivators or corepressors. The ER-estrogen complex, afer binding to DNA, can also bind a protein coactivator, which activates transcriptoin. Likewise binding of a corepressor to the DNA-bound complex inhibits transcriptional activity. Tamoxifen binding to the ERα monomer leads to dimerization and DNA binding. The DNA-bound dimer can then bind either a corepressor (the usual case for tamoxifen binding to ER in breast), leading to inhibition of DNA transcription (i.e. tamoxifen antagonizes ER transcriptional function), or a coactivator which stimulates gene transcription.

    A cartoon diagram illustrating the role of ER coactivators and corepressors is shown in Figure \(\PageIndex{11}\) below.

    Breast-related_effects_of_selective_estrogen_recepFig2.svg
    Figure \(\PageIndex{11}\): Molecular activity of selective estrogen receptor modulators (SERMs) at estrogen receptors. Smith et al. ibid

    When a SERM binds to the estrogen receptor, the receptor adopts a unique conformation that allows dimerization and interaction with estrogen response elements (EREs) of thetarget genes. The unique conformational change induced by binding of the SERM may result in a distinct pattern of cofactor recruitment.

    Before steroid binding, most steroid receptors are found in the cytoplasm bound to heat shock proteins like Hsp90. Phosphorylation of the Hsp:SR complex leads to dissociation of the Hsp, followed by dimerization and translocation into the nucleus. In some cases, hormone binding occurs in the nucleus.

    Figure \(\PageIndex{12}\) below shows an interactive iCn3D model of the estrogen receptor DNA-binding domain bound to DNA (1HCQ).

    1HCQ_DNA_ERbinding.png
    Figure \(\PageIndex{12}\): Estrogen receptor DNA-binding domain bound to DNA (1HCQ) (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...rUUhnx8J8ezh8A

    The backbones of the dsDNA ae showing in spacefill cyan and magenta. The DNA bases are shown in CPK colors. The two chains of the DNA binding domain of estrogen receptor are shown in gray and gold. Zn2+ ions are shown as brown spheres. The coordinating Cys side chains in the gray DNA binding domain are shown in sticks, CPK colors and labeled "C". The amino acid side chains from the gold DNA binding domain that interact withe DNA are shown in sticks CPK colors.

    There are two types of ways that steroid hormones activate gene transcription, a direct and an indirect method

    Direct (classical): The DNA binding domain (containing the Zn fingers binds) of the dimer bind to target hormone response element (HRE) or for steroids the steroid response element (SRE) sequences in the promoter site of specific genes under steroid hormone control. As seen in the iCn3D above, one of the two Zn fingers on each of the hormone receptors binds to the target site in the major groove of DNA. The other Zn fingers are involved in dimerization of the hormone receptor. The SRE contains two 6 base pair repeats separated by 3 base pairs. The DNA sequence shown in the iCn3D above is CCAPGGTCA. The general consensus sequence for steroid hormones is 5′-GGTACAnnnTGTTCT-3′. The ER binds to 5′-GGTCAnnnTGACC-3′. Note that the complementary strand sequence is 5'-GGTCAnnTGACC so the sequence is a palindrome (the complementary strand has the same sequence going in the opposite direction. After binding of the hormone:receptor dimer to DNA, coregulators bind. These modify histones and remodel the DNA to facilitate or inhibit transcription.

    Indirect: In this method, the steroid receptors bridges other DNA-bound transcription factors without the steroid hormone binding to its response element.

    The direct and indirect methods for steroid hormone effects on transcription are shown in Figure \(\PageIndex{13}\) below.

    SteroidReceptorsBreastCancerFig3.svg
    Figure \(\PageIndex{13}\): SR synthesis, genomic signaling and degradation.

    (1) Translation of a SR and binding of Hsp70. (2) Hsp70 to Hsp90 transition. (3) Ligand binding, Hsp90 dissociation and dimerization. (4) Nuclear translocation. (5) Transcriptional action: induction (5a, 5c) or inhibition (5b, 5d) of target gene expression, performed either in the classical mechanism involving SRE-binding (5a, 5b) or by tethering other TFs (5c, 5d). (6) Ligand dissociation followed by disassembly of the transcriptional complex and SR binding to a molecular chaperone. (7) Rebinding of the ligand. (8) Ubiquitination. (9) Proteasomal degradation. SR—steroid receptor, SH—steroid hormone, Hsp 70—heat shock protein 70, Hsp90—heat shock protein 90, SRE—steroid response element, CoA—coactivators, CoR—corepressors, HAT—histone acetyltransferase, HDAC—histone deacetylase, TF—transcription factor, TFRE—transcription factor response element, Ub—ubiquitin. Although histone acetyl transferases (HATs) and histone deacetylases (HDACs) are classified as coregulators, here they are shown separately in order to emphasize their role. Illustration created using elements from Servier Medical Art https://smart.servier.com/, reproduced under Creative Commons Attribution 3.0 Unported License https://creativecommons.org/licenses/by/3.0/.

    Hormone dissociation lead to steroid hormone dissociation from DNA by chaperone proteins. The Hsp90-SR complex can reenter the cycle. The steroid hormone receptor can be targeted by proteolysis by the proteasome by ubiquitination in either the nucleus or the cytoplasm.

    Modulation of ER function by phosphorylation

    No pathways stands in isolation, so it should be no surprise the estrogen receptor (again used as a example) is regulated by post-translational modification, especially by phosphorylation. Phosphorylation can be ligand dependent or independent. Multiple kinases are involved in phosphorylation of the N-terminal region. An especially important one occurs at Ser 118 at a cyclin dependent kinase (involved in cell cycling) when the receptor is bound to estradiol. Ser 118 also gets phosphorylation through epidermal growth factor signaling by MAPK. This may increase cell proliferation in breast cancers even in the absence of estrogen. Figure \(\PageIndex{14}\) shows the activation of ER by phosphorylation through growth factor and cytokine signaling pathways.

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    Figure \(\PageIndex{14}\): Activation of ER by phosphorylation induced by growth factor and cytokine signaling pathways. Siersbæk et al , 2018 Sep 1; 32(17-18): 1141–1154. doi:10.1101/gad.316646.118. Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.


    12.11: Signaling by Steroid Hormones is shared under a not declared license and was authored, remixed, and/or curated by Henry Jakubowski and Patricia Flatt.

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