Aberrant activation of canonical Notch1 signaling in the mouse prostate drives epithelialcell proliferation and induces prostatic hyperplasiaby increasing androgen receptor sensitivity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA825375 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18708990_1.fastq.gz | Fastqsanger.gz | |||
| SRR18708990_2.fastq.gz | Fastqsanger.gz | |||
| SRR18708991_1.fastq.gz | Fastqsanger.gz | |||
| SRR18708991_2.fastq.gz | Fastqsanger.gz | |||
| SRR18708992_1.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the regulatory role of Notch1 signaling pathway in mouse prostate growth and development, we constructed mice with prostate-specific overactivation of Notch1 intracellular domain N1ICD, in which Notch1 signaling was overactivated in prostate epithelial cells. We then analyzed gene expression profiles in the prostates of overexpressed and normal Notch1 mice.
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Project description:Molecular signaling that regulates differentiation, survival and proliferation of the prostate luminal epithelial cells has not been thoroughly understood. Herein, we show that increased canonical Notch1 activity suppresses terminal differentiation of prostate luminal epithelial cells but is insufficient to transform. Augmented Notch1 activity delays anoikis of luminal epithelial cells by augmenting NF-κB activity independent of Hes-1, stimulates luminal cell proliferation by potentiating the PI3K-AKT signaling, and rescues the capacities of a fraction of prostate luminal epithelial cells for unipotent differentiation in vivo and short-term self-renewal in vitro. Epithelial cell-autonomous AR signaling is dispensable for the Notch-mediated cellular survival and proliferation. This study reveals a previously unappreciated role of Notch in prostatic luminal epithelial cell differentiation, supports the presence of a lineage hierarchy within the prostate luminal epithelial cells, and implies a pro-metastatic function of Notch signaling during prostate cancer progression. Two group comparison (WT and Mut)
2014-08-07 | E-GEOD-53036 | biostudies-arrayexpress
Project description:Molecular signaling that regulates differentiation, survival and proliferation of the prostate luminal epithelial cells has not been thoroughly understood. Herein, we show that increased canonical Notch1 activity suppresses terminal differentiation of prostate luminal epithelial cells but is insufficient to transform. Augmented Notch1 activity delays anoikis of luminal epithelial cells by augmenting NF-κB activity independent of Hes-1, stimulates luminal cell proliferation by potentiating the PI3K-AKT signaling, and rescues the capacities of a fraction of prostate luminal epithelial cells for unipotent differentiation in vivo and short-term self-renewal in vitro. Epithelial cell-autonomous AR signaling is dispensable for the Notch-mediated cellular survival and proliferation. This study reveals a previously unappreciated role of Notch in prostatic luminal epithelial cell differentiation, supports the presence of a lineage hierarchy within the prostate luminal epithelial cells, and implies a pro-metastatic function of Notch signaling during prostate cancer progression.
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Project description:Macrophages exhibit marked phenotypic heterogeneity within and across disease states. Lipid metabolic reprogramming critically regulates macrophage activation. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate as prostate size increases. No T cell subclusters specifically accumulate in large versus small prostates. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and prostatic symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages localize to the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define new BPH immune subpopulations, TREM2+ and MARCO+ macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.
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Project description:Notch signaling activation drives endothelial-to-mesenchymal transition (EndMT), which is key to heart development. Accumulating evidence indicates that endothelial cell metabolism reprogramming regulates endothelial function independent of canonical cell signaling. Herein, we investigated whether and how Notch signaling and metabolism reprogramming crosstalk in the EndMT process. We found Notch1 intracellular domain (NICD1) was localized within the mitochondria of endothelial cells and interacted with the PDH E1 subunit beta, influencing the phosphorylation of the PDH E1 subunit alpha, thereby activating PDH and enhancing mitochondrial metabolism.
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