SummaryAge-related thymic involution may be triggered by gene expression changes in lymphohematopoietic and ⁄ or nonhematopoietic thymic epithelial cells (TECs). The role of epithelial cell-autonomous gene FoxN1 may be involved in the process, but it is still a puzzle because of the shortage of evidence from gradual loss-of-function and exogenous gain-of-function studies. Using our recently generated loxP-floxed-FoxN1(fx) mouse carrying the ubiquitous CreER T (uCreER T ) transgene with a low dose of spontaneous activation, which causes gradual FoxN1 deletion with age, we found that the uCreER T -fx ⁄ fx mice showed an accelerated age-related thymic involution owing to progressive loss of FoxN1 + TECs. The thymic aging phenotypes were clearly observable as early as at 3-6 months of age, resembling the naturally aged (18-22-month-old) murine thymus. By intrathymically supplying aged wild-type mice with exogenous FoxN1-cDNA, thymic involution and defective peripheral CD4 + T-cell function could be partially rescued. The results support the notion that decline of a single epithelial cell-autonomous gene FoxN1 levels with age causes primary deterioration in TECs followed by impairment of the total postnatal thymic microenvironment, and potentially triggers agerelated thymic involution in mice.
Understanding the pathways that are targeted by cancer drugs is instrumental for their rational use in a clinical setting. Inhibitors of histone deacetylases (HDACI) selectively inhibit proliferation of malignant cells and are used for the treatment of cancer, but their cancer selectivity is understood poorly. We conducted a functional genetic screen to address the mechanism(s) of action of HDACI. We report here that ectopic expression of two genes that act on retinoic acid (RA) signaling can cause resistance to growth arrest and apoptosis induced by HDACI of different chemical classes: the retinoic acid receptor ␣ (RAR␣) and preferentially expressed antigen of melanoma (PRAME), a repressor of RA signaling. Treatment of cells with HDACI induced RA signaling, which was inhibited by RAR␣ or PRAME expression. Conversely, RAR-deficient cells and PRAME-knockdown cells show enhanced sensitivity to HDACI in vitro and in mouse xenograft models. Finally, a combination of RA and HDACI acted synergistically to activate RA signaling and inhibit tumor growth. These experiments identify the RA pathway as a rate-limiting target of HDACI and suggest strategies to enhance the therapeutic efficacy of HDACI.biomarker ͉ chromatin modification ͉ drug resistance ͉ epigenetics ͉ nuclear hormone receptor E pigenetic DNA and histone modifications are appreciated as major determinants in the control of gene activity, and they are extensively deregulated in cancer. Histone acetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs), which catalyze the addition and removal of acetyl groups to histones, respectively, and to a growing list of nonhistone substrates (1). The activities of HATs and HDACs are altered in several human cancers, and modulation of these classes of enzymes provides a potentially attractive therapeutic modality (2, 3). Several classes of HDAC inhibitors (HDACI) have been identified that block enzyme activity, resulting in global histone hyperacetylation. A wide array of literature on HDACI exists, describing their various effects, including G 1 and G 2 /M cell cycle arrests, apoptosis, and differentiation, and several HDACI have entered clinical trials (2-4). Gene expression profiling studies revealed that HDACI treatment induces alterations in transcription of Ͻ5% to Ϸ20% of expressed genes (5, 6) and have not elucidated a consistent picture of the pathway(s) or target(s) that are modulated by HDACI and, consequently, have not provided a comprehensive explanation for their anticancer effects.To identify cellular targets of HDACI action in transformed cells, we used the approach of large-scale functional genetic screening. In this screen we asked which genes or pathways could confer cellular resistance to HDACI. The present work provides evidence that the retinoic acid receptor (RAR) pathway is targeted by HDACI and that the cytotoxic effects of HDACI in solid tumor cells are, at least in part, through derepression of retinoic acid (RA) signaling.
ResultsGe...
This approach may give direction to future research aimed at precisely mapping loci altered in DCIS and help in understanding the biologic events associated with tumor progression or recurrence.
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