Nuclear receptor liver receptor homologue 1 (LRH-1) regulates pancreatic cancer cell growth and proliferation.

An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium.

Molecular basis for dimer formation of TRbeta variant D355R.

Protein quality and stability are critical during protein purification for X-ray crystallography. A target protein that is easy to manipulate and crystallize becomes a valuable product useful for high-throughput crystallography for drug design and discovery. In this work, a single surface mutation, D355R, was shown to be crucial for converting the modestly stable monomeric ligand binding domain of the human thyroid hormone receptor (TR LBD) into a stable dimer.

Interaction between the androgen receptor and a segment of its corepressor SHP.

The mechanisms of functional repression of the androgen receptor (AR) are crucial for the regulation of genes involved in physiological development as well as for the progression of prostate cancer. To date, only two in vivo inhibitors of AR-mediated transcription have been identified: DAX-1 and SHP (small heterodimer partner). SHP is a regulatory nuclear receptor (NR) that lacks DNA-binding and activation domains.

Perspectives on designs of antiandrogens for prostate cancer.

The androgen receptor (AR) regulates gene transcription in many tissues and is profoundly important in prostate cancer. Antiandrogens compete with the natural hormone and are front line therapeutics to treat prostate cancer. However, antiandrogens frequently become ineffective after prolonged treatment because of development of tumor resistance.

Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic beta-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor beta (TRbeta), in a high-throughput screen. Initial evidence suggested that the aromatic beta-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRbeta surface, is liberated from DHPPA.

Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators.

Thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) is an endocrine hormone that exerts homeostatic regulation of basal metabolic rate, heart rate and contractility, fat deposition, and other phenomena (1, 2). T3 binds to the thyroid hormone receptors (TRs) and controls their regulation of transcription of target genes. The binding of TRs to thyroid hormone induces a conformational change in TRs that regulates the composition of the transcriptional regulatory complex.