Androgen Receptor in Health and Disease

Marcelli, Marco

doi:10.1007/978-3-319-46086-4_2

Cited by 3 publications

(6 citation statements)

References 302 publications

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“…The first is closer to the NTD, has the P box, and controls the DNA binding specificity at specific DNA sequences ( Figure 2 ). These sequences are typically identified as androgen response elements (AREs), cis-acting sequences located in the regulatory regions of genes [ 31 ]. The second zinc finger motif facilitates AR dimerization via the D box [ 32 ].…”

Section: Structure Of the Androgen Receptormentioning

confidence: 99%

“…In the cytoplasm, the inactive, unliganded, full-length AR monomer is bound to heat shock proteins (HSP) 90, 70, and 40 of the HSP chaperone complex, protecting the AR from degradation ( Figure 4 A) [ 40 ]. Upon androgen binding at the LBD, the monomeric AR undergoes a conformational change, allowing its dissociation from HSP-90, -70 and -40 and association with HSP27 [ 9 , 14 , 15 , 21 , 31 , 41 , 42 , 43 ]. One model suggests this conformational change prompts phosphorylation of the AR resulting in an intramolecular interaction between the NTD and LBD ( Figure 4 B), exposing the nuclear localization signal and allowing subsequent entry into the nucleus through the nuclear pore complex ( Figure 4 C) [ 24 , 44 ].…”

Section: The Spaciotemporal Regulation Of Ar Transcriptional Activmentioning

confidence: 99%

“…The D-box regions bind to the partner monomer (DBD–DBD interaction), and the P-box regions of each AR monomer binds to the target DNA ( Figure 4 D) [ 42 ]. The DBD–DBD “head-to-head” homodimer ( Figure 4 E) [ 23 , 42 , 44 ] forms at AREs defined either by the canonical two hexameric palindromic half-site sequence 5′-AGAACA-NNN-TGTTCT-3′, or by the AR-specific two hexameric direct repeat sequence 5′-AGAACA-NNN-AGAACA-3′ [ 25 , 31 ]. LBD-LBD homodimers (not shown) may also form in an androgen-dependent manner, but the spaciotemporal regulation of this dimer is yet to be uncovered.…”

Section: The Spaciotemporal Regulation Of Ar Transcriptional Activmentioning

confidence: 99%

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The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

et al. 2020

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The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development.

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Section: Structure Of the Androgen Receptormentioning

confidence: 99%

Section: The Spaciotemporal Regulation Of Ar Transcriptional Activmentioning

confidence: 99%

Section: The Spaciotemporal Regulation Of Ar Transcriptional Activmentioning

confidence: 99%

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The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

et al. 2020

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“…Their actions are mediated through the androgen receptor (AR) activation (R.‐S. Wang, Yeh, Tzeng, & Chang, 2009), which in turn binds to the androgen‐responsive element and regulates the transcription of the target genes (Marcelli, 2017). Downregulation of androgens has been linked to the failure of the spermatogenesis process (Marcelli, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Wang, Yeh, Tzeng, & Chang, 2009), which in turn binds to the androgen‐responsive element and regulates the transcription of the target genes (Marcelli, 2017). Downregulation of androgens has been linked to the failure of the spermatogenesis process (Marcelli, 2017). AR is an X chromosome gene located on the long arm, composed of eight exons and reported to have many mutations that affect spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

CAG Repeats in the androgen receptor gene is associated with oligozoospermia and teratozoospermia in infertile men in Jordan

et al. 2020

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CAG trinucleotide repeats are coded for the polyglutamine tract in the N-terminal of the androgen receptor (AR) gene which varies in normal individuals from 6 to 36 residues. In this study, we inspected the impact of the CAG repeats on the spermatogenic defects by measuring the size of AR-CAG repeats length in a cohort of 260infertile and 169 fertile Jordanian men. The infertile group included three subgroups of a zoospermic, oligozoospermic and teratozoospermia men. The CAG allele size was determined by direct sequencing. The results showed a significant association between the length of the AR-CAG repeats and men's infertility (p = .001). In particular, the current cohort demonstrated a significant association between the AR-CAG length polymorphism and oligozoospermia (p < .001) and teratozoospermia (p < .001) but not azoospermia. According to distributions of allele frequency, the risk of oligozoospermia was 5.5-fold greater than normal when alleles frequency > 20 repeats, while the risk of teratozoospermia was > 10.6 folds greater than normal when allele frequency > 22 repeats. In conclusion, our results underscored that the long repeats of the AR-CAG polymorphism within the normal range might be associated with abnormal spermatogenesis such as teratozoospermia and oligozoospermia and contributing to infertility in Jordanian men.

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Androgen signalling in the ovaries and endometrium

Lissaman

Girling

Cree

et al. 2023

Molecular Human Reproduction

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Currently, our understanding of hormonal regulation within the female reproductive system is largely based on our knowledge of estrogen and progesterone signalling. However, while the important functions of androgens in male physiology are well known, it is also recognised that androgens play critical roles in the female reproductive system. Further, androgen signalling is altered in a variety of gynaecological conditions, including endometriosis and PCOS, indicative of regulatory roles in endometrial and ovarian function. Co-regulatory mechanisms exist between different androgens, estrogens, and progesterone, resulting in a complex network of steroid hormone interactions. Evidence from animal knockout studies, in vitro experiments, and human data indicates that the androgen receptor expression is cell-specific and menstrual cycle stage-dependent, with important regulatory roles in the menstrual cycle, endometrial biology, and follicular development in the ovaries. This review will discuss the expression and co-regulatory interactions of androgen receptors, highlighting the complexity of the androgen signalling pathway in the endometrium and ovaries, and the synthesis of androgens from additional alternative pathways previously disregarded as male-specific. Moreover, it will illustrate the challenges faced when studying androgens in female biology, and the need for a more in-depth, integrative view of androgen metabolism and signalling in the female reproductive system.

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Androgen Receptor in Health and Disease

Cited by 3 publications

References 302 publications

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

CAG Repeats in the androgen receptor gene is associated with oligozoospermia and teratozoospermia in infertile men in Jordan

Androgen signalling in the ovaries and endometrium

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