Identification of a Novel Coregulator, SH3YL1, That Interacts With the Androgen Receptor N-Terminus.

Nuclear receptor (NR)-mediated transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in the NR. These structural alterations lead to the differential recruitment of coregulators (coactivators or corepressors) that control the expression of NR-regulated genes. Here, we show that a stretch of proline residues located within the N-terminus of androgen receptor (AR) is a bona fide coregulator binding surface, the disruption of which reduces the androgen-dependent proliferation and migration of prostate cancer (PCa) cells.

Improved bone morphogenetic protein-2 retention in an injectable collagen matrix using bifunctional peptides.

To promote healing of many orthopedic injuries, tissue engineering approaches are being developed that combine growth factors such as Bone Morphogenetic Proteins (BMP) with biomaterial carriers. Although these technologies have shown great promise, they still face limitations. We describe a generalized approach to create target-specific modular peptides that bind growth factors to implantable biomaterials.

Pharmacological uncoupling of androgen receptor-mediated prostate cancer cell proliferation and prostate-specific antigen secretion.

The androgen receptor (AR), a member of the nuclear receptor family, is a ligand-inducible transcription factor. In the prostate gland, androgens regulate the transcription of several genes that ultimately result in cell growth and differentiation. With a goal of developing tissue-selective AR modulators that can be used to treat prostate cancer and other androgenopathies, we have taken an approach to identify androgens that function in a manner distinct from the physiological androgens testosterone and dihydrotestosterone.

Identification and characterization of novel estrogen receptor-beta-sparing antiprogestins.

The steroid hormones estrogen and progesterone together regulate the development and maintenance of the female reproductive system. The actions of these two hormones are mediated by their respective nuclear receptors located within overlapping cell populations in target organs. The molecular mechanism of action of these two hormones has been defined to a large extent using estrogen receptor (ER) and progesterone receptor (PR) antagonists.

Structural regions of ERalpha critical for synergistic transcriptional responses contain co-factor interacting surfaces.

Most highly estrogen responsive genes are synergistically activated by multiple copies of estrogen responsive elements (EREs) capable of binding to the estrogen receptor (ER). We examined here the structural features of the receptor necessary to interact with co-regulatory proteins and to produce a synergistic pattern of activation from multiple EREs. Using full length and truncated variants of ERalpha, we show in transfected mammalian cells that although the carboxyl (AF-2) and the amino (AF-1) terminal activation domains are functionally integrated to induce transcription, AF-1 is critical for mediating synergy.