Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiling of mouse prostate over-expressing the Notch1 intracellular domain.

ABSTRACT: 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)

ORGANISM(S): Mus musculus

SUBMITTER: Chad Creighton

PROVIDER: E-GEOD-53036 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells.

Kwon Oh-Joon OJ Valdez Joseph M JM Zhang Li L Zhang Boyu B Wei Xing X Su Qingtai Q Ittmann Michael M MM Creighton Chad J CJ Xin Li L

Nature communications 20140722

The prostate epithelial lineage hierarchy remains inadequately defined. Recent lineage-tracing studies have implied the existence of prostate luminal epithelial progenitors with extensive regenerative capacity. However, this capacity has not been demonstrated in prostate stem cell activity assays, probably owing to the strong susceptibility of luminal progenitors to anoikis. Here we show that constitutive expression of Notch1 intracellular domain impairs secretory function of mouse prostate lumi ...[more]

PMID: 25048699

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Project description:The signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined. To further understand the role of Notch signaling during endothelial differentiation, this study uses both an in vivo gain-of-function and in vivo loss-of-function approach. At embryonic day 9.5, embryos with activated Notch1 signaling in the endothelia display a variety of growth and cardiovascular defects, and die soon after E10.5. Most notably, the extra-embryonic vasculature of the yolk sac displays remodeling differentiation defects. In the wild-type yolk sac, the primary vascular network has begun to reorganize, forming the large primary vessels and the smaller capillaries. In the activated Notch1 embryos remodeling is defective; the vasculature have an enlarged surface with decreased inter-vessel space. Embryos with ablated Notch signaling also display growth and vascular defects at E9.5 similar to the activated Notch1 embryos, however they exhibit a lack of vascular remodeling in the yolk sac, retaining the simple vascular plexus seen at E8.5. These results indicate that Notch signaling plays a critical role in the remodeling of the vasculature in the early embryo, particularly in the extra embryonic region. A conditional transgenic system was used in this study to activate Notch signaling. The ubiquitous ROSA26Notch transgene with a Neo/stop cassette flanked by loxP sites, followed by the N1-ICD cDNA, was recombined with a Tie2-CRE mouse, resulting in the removal of the STOP cassette and the subsequent activation of the Notch1-intracellular domain. This allowed for the overexpression and expansion of Notch signaling in all endothelial cells. Male Tie2-Cre mice were mated with female ROSA26Notch mice and resulting embryos were dissected at embryonic day 9.5. To ablate Notch signaling, Tie2-Cre mice were used in a two generation cross to obtain Tie2-Cre; Rbpj flox/flox embryos. These embryos lack RBPJ binding activity in the endothelia. In both instances embryos were used for genotyping and the yolk sac were separated and used to isolate total RNA with an RNeasy mini kit. The RNA was analyzed with the Mouse Genome 430A Array from Affymetrix. Samples were performed in duplicate, and RNA from wild type yolk sac tissues was compared to activated Notch and RBPJ loss-of-function yolk sac tissues.

Dataset Information

Gene expression profiling of mouse prostate over-expressing the Notch1 intracellular domain.

Publications

Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells.

Similar Datasets

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