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We have identified and characterized a new amphibian orphan member of the nuclear receptor superfamily and termed it FOR1 (farnesoid X receptor (FXR)-like OrphanReceptor) because it shares the highest amino acid identity with the mammalian FXR. We also identified a variant of FOR1, called FOR2, which has 15 additional C-terminal amino acids. Both variants include an unusual insertion of 33 amino acids in the helix 7 region of the canonical ligand binding domain sequence, suggesting a unique structure for FOR. Northern blot analysis demonstrates that the FORgene is highly expressed in adult and tadpole liver, kidney, and tail bud stage of the embryo. Detailed expression analysis using in situhybridization indicates that FOR expression is first detectable at stage 30/31 in the presumptive liver region lasting until stage 41 with a peak level evident at stage 35/36. FOR forms heterodimeric complexes with retinoid X receptor (RXR) as demonstrated by biochemical and mammalian two-hybrid approaches. Gel mobility shift assays demonstrate that FORs form specific DNA-protein complexes on an FXR binding element consisting of an inverted repeat DNA element with 1 nucleotide spacing (IR1) from the phospholipid transfer proteingene promoter. Finally, although FORs do not exhibit constitutive transcriptional activity, frog gallbladder extract significantly augments the transcriptional activities of FORs.

The orphan nuclear receptor small heterodimer partner (SHP; NR0B2) interacts with a wide array of nuclear receptors and represses their transcriptional activity. SHP expression is regulated by several other members of the nuclear receptor superfamily, including the orphan receptors SF-1 and LRH-1, and the bile acid receptor FXR. We have found that the SHPpromoter is also activated by the estrogen receptor-related receptor γ (ERRγ) but not the related ERRα and ERRβ isoforms. SHP and ERRγ mRNAs are coexpressed in several tissues, including pancreas, kidney, and heart, confirming the potential relevance of this transactivation. ERRγ transactivation is dependent on only one of five previously characterized DNA-binding sites for SF-1, and this element differs from previously reported ERR response elements. However, treatment with the histone deacetylase inhibitor trichostatin A significantly increased ERRα and ERRβ activity on this element indicating that the lack of activity of ERRα and -β may depend on their association with co-repressor in vivo. Furthermore, using protease sensitivity assays on DNA bound receptors it was demonstrated that DNA sequence of different response elements may cause allosteric modulation of ERR proteins, which in turn may be responsible for the differential activities of these receptors on different response elements. SHP inhibits ERRγ transactivation and physically interacts with all three members of ERR subfamily, as demonstrated by both yeast two-hybrid and biochemical assays. As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRγ and the previously described N-terminal receptor interaction domain of SHP. Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRγ activity. Overall, these results identify a new autoregulatory loop controlling SHPgene expression and significantly extend the potential functional roles of the three ERRs.

Mantle Cell Lymphoma (MCL) is a difficult to cure, highly heterogeneous, and aggressive form of non-Hodgkin lymphoma comprising roughly 7% of all cases with a high recurrence rate and poor long-term prognosis. The reported progression-free survival is about 1-2 years, and median overall survival/OS <3 years. Current first-line MCL therapies include combination regimens like R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP, etc. However, although patients respond well to initial treatment, most eventually progress to relapsed disease state. BTKis (Bruton's tyrosine kinase inhibitors) such as Ibrutinib are standard targeted therapeutic options for refractory or relapsed (R/R) MCL. The proteasome inhibitor (PI) drug Bortezomib/Velcade/Bz is another FDA-approved targeted drug for R/R MCL. However, despite these recent advances in the treatment landscape, R/R MCL still remains incurable with limited therapeutic options and a median OS<10-15 months. Therefore, there is an unmet need to discover novel drugs against R/R MCL.

No relevant conflicts of interest to declare.