Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

Abstract

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer, the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible to develop than others due to the ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

Conserved functional motifs of the nuclear receptor superfamily as potential pharmacological targets

“…5) and motif C, occupying positions 972-982 (Fig. 5), as reported in the literature, also appear to be regions necessary for co-activator function (25). Motif D, which occupies positions 1051-1063 of the steroid receptor multiple alignment (Fig.…”

“…Motif D, which occupies positions 1051-1063 of the steroid receptor multiple alignment (Fig. 5), appears to be highly conserved and is an area of utmost significance for ligand binding, as mutations in this area have been proven to lead to the complete inability of the receptor to bind (22,24,25). Finally, in alignment positions 1115-1122, a LxxLL motif is observed (motif E), whereas in alignment positions 1144-1153, an inverse NR box (LLxxL) can be found, named motif F (Fig.…”

Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3

“…An in silico search of the 410 aa NR2E3 protein sequence (NP_055064.1) for an NLS using the database cNLS mapper [ 44 ], identified a putative, but low-score, bipartite NLS at aa position 69 in the DBD. Consistently, other members of the Nuclear Receptor family are known to contain NLS in the DBD, in the hinge region, or even the LBD [ 45 , 46 ]. The predicted NLS in the NR2E3 DBD is missing from the truncated G56R-CRISPR proteins, which could account for the lack of nuclear targeting.…”

“…These results could suggest that NR2E3 shuttles between the nucleus and the cytoplasm to accomplish its roles in the cell. This would not be surprising, as many nuclear receptors are known to reside in the cytoplasm [ 46 ], but, until now, it has not been described for NR2E3. Different mechanisms have been reported for the export of nuclear receptors, including nuclear export signals (NES), protein–protein interactions, and posttranslational modifications [ 47 ].…”

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

“…The AR gene is located on the long arm of the X-chromosome and is expressed in several tissues, including the prostate, breast, testes, skeletal muscle, uterus, and bladder [ 11 ]. The AR belongs to the family of transcription factors that homodimerize after ligand-binding, while RXR receptors may heterodimerize, and monomeric orphan receptors do not require dimerization [ 12 , 13 ].…”