Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface

Prostate cancer is a leading killer of men in the industrialized world. Underlying this disease is the aberrant action of the androgen receptor (AR). AR is distinguished from other nuclear receptors in that after hormone binding, it preferentially responds to a specialized set of coactivators bearing aromatic-rich motifs, while responding poorly to coactivators bearing the leucine-rich “NR box” motifs favored by other nuclear receptors. Under normal conditions, interactions with these AR-specific coactivators through aromatic-rich motifs underlie targeted gene transcription. However, during prostate cancer, abnormal association with such coactivators, as well as with coactivators containing canonical leucine-rich motifs, promotes disease progression. To understand the paradox of this unusual selectivity, we have derived a complete set of peptide motifs that interact with AR using phage display. Binding affinities were measured for a selected set of these peptides and their interactions with AR determined by X-ray crystallography. Structures of AR in complex with FxxLF, LxxLL, FxxLW, WxxLF, WxxVW, FxxFF, and FxxYF motifs reveal a changing surface of the AR coactivator binding interface that permits accommodation of both AR-specific aromatic-rich motifs and canonical leucine-rich motifs. Induced fit provides perfect mating of the motifs representing the known family of AR coactivators and suggests a framework for the design of AR coactivator antagonists

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Model of tumor dormancy/recurrence after short-term chemotherapy.

Although many tumors regress in response to neoadjuvant chemotherapy, residual tumor cells are detected in most cancer patients post-treatment. These residual tumor cells are thought to remain dormant for years before resuming growth, resulting in tumor recurrence. Considering that recurrent tumors are most often responsible for patient mortality, there exists an urgent need to study signaling pathways that drive tumor dormancy/recurrence. We have developed an in vitro model of tumor dormancy/recurrence. Short-term exposure of tumor cells (breast or prostate) to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from "recurrent" colonies exhibit increased chemotherapy resistance, similar to the therapy resistance of recurrent tumors in cancer patients. Previous studies using long-term chemotherapy selection models identified acquired mutations that drive tumor resistance. In contrast, our short term chemotherapy exposure model enriches for a slow-cycling, dormant, chemo-resistant tumor cell sub-population that can resume growth after drug removal. Studying unique signaling pathways in dormant tumor cells enriched by short-term chemotherapy treatment is expected to identify novel therapeutic targets for preventing tumor recurrence

Do local unemployment rates modify the effect of individual labour market status on psychological distress?

This study investigates whether the unemployment rate of the area in which an individual lives affects their level of psychological distress, and the extent to which this is dependent on their own labour market status. Data were taken from the British Household Panel Survey (1991-2008) and longitudinal multiple membership multilevel modelling was carried out in order to account for the complex hierarchical structure of the data. The results suggest that living in an area with a high unemployment rate, defined by the claimant count, confers a degree of protection against the negative psychological effects of unemployment. However, psychological distress levels among unemployed people were still significantly and substantially higher than among their securely employed counterparts

Surface Complimentarity of Hydrophobic Motifs in the AR, ERα, and GR AF-2 Clefts

<p>(A) AR–FxxLF, (B)AR–LxxLL, (C) ERα–GRIP1 (LxxLL) (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020274#pbio-0020274-Shiau1" target="_blank">Shiau et al. 1998</a>), and (D) GR-TIF2 (LxxLL) (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020274#pbio-0020274-Bledsoe1" target="_blank">Bledsoe et al. 2002</a>). The inside surfaces of the AF-2 cleft in AR, ERα, and GR are depicted. The LBD is additionally shown as a Cα trace with key side chains shown as white sticks. Phenylalanines and leucines of the FxxLF and LxxLL motifs are shown as spheres.</p

Interactions of FxxYF and FxxFF with the AR LBD

<p>FxxYF (A) and FxxFF (B) bound to the AR AF-2 interface. FxxYF and FxxFF are shown as yellow and orange Cα coils, respectively. The LBD is depicted as in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020274#pbio-0020274-g003" target="_blank">Figure 3</a>.</p