Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone-independent state termed castration-resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten mice, generated by luminal epithelial cell-specific deletion of the tumor suppressor PTEN after puberty, is castration-resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells.
View Article and Find Full Text PDFProstate cancer (PCa) is a leading cause of cancer-related deaths. The slow evolution of precancerous lesions to malignant tumors provides a broad time frame for preventing PCa. To characterize prostatic intraepithelial neoplasia (PIN) progression, we conducted longitudinal studies on Pten mice that recapitulate prostate carcinogenesis in humans.
View Article and Find Full Text PDFVitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility.
View Article and Find Full Text PDFThe nuclear retinoic acid (RA) receptors (RARα, β and γ) are ligand-dependent regulators of transcription. Upon activation by RA, they are recruited at the promoters of target genes together with several coregulators. Then, they are degraded by the ubiquitin proteasome system.
View Article and Find Full Text PDFRetinoic acid receptors (RARs) are classically considered as nuclear ligand-dependent regulators of transcription. Here we highlighted a novel face of the RARα subtype: RARα is present in low amounts in the cytoplasm of mouse embryonic fibroblasts (MEFs) where it interacts with profilin2a (PFN2A), a small actin-binding protein involved in filaments polymerization. The interaction involves the N-terminal proline-rich motif (PRM) of RARα and the SH3-like domain of PFN2a.
View Article and Find Full Text PDFRetinoic acid (RA) plays key roles in cell differentiation and growth arrest through nuclear retinoic acid receptors (RARs), which are ligand-dependent transcription factors. While the main trigger of RAR activation is the binding of RA, phosphorylation of the receptors has also emerged as an important regulatory signal. Phosphorylation of the RARγ N-terminal domain (NTD) is known to play a functional role in neuronal differentiation.
View Article and Find Full Text PDFRetinoic acid (RA), the main active vitamin A metabolite, controls multiple biological processes such as cell proliferation and differentiation through genomic programs and kinase cascades activation. Due to these properties, RA has proven anti-cancer capacity. Several breast cancer cells respond to the antiproliferative effects of RA, while others are RA-resistant.
View Article and Find Full Text PDFNuclear retinoic acid (RA) receptors (RARα, β and γ) are ligand-dependent transcription factors that regulate the expression of a battery of genes involved in cell differentiation and proliferation. They are also phosphoproteins and we previously showed the importance of their phosphorylation in their transcriptional activity. In the study reported here, we conducted a genome-wide analysis of the genes that are regulated by RARs in mouse embryonic fibroblasts (MEFs) by comparing wild-type MEFs to MEFs lacking the three RARs.
View Article and Find Full Text PDFGene activation by retinoic acid nuclear receptors (RAR) is regulated by a number of molecular events such as ligand binding, interaction with cognate DNA sequences and co-regulatory proteins, and phosphorylation. Among the several phosphorylation sites that are involved in the non-genomic regulatory pathways of the RAR, two are located in a proline rich domain (PRD) within the N-terminal domain (NTD) of the receptor. This region is predicted to be intrinsically disordered, complicating its production and purification.
View Article and Find Full Text PDF