Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC
AffiliationUniv Arizona, Ctr Canc, Dept Cellular & Mol Med
MetadataShow full item record
PublisherCOMPANY OF BIOLOGISTS LTD
CitationHuman prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC 2017, 130 (11):1952 Journal of Cell Science
JournalJournal of Cell Science
Rights© 2017. Published by The Company of Biologists Ltd
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AbstractMany pathways dysregulated in prostate cancer are also involved in epithelial differentiation. To better understand prostate tumor initiation, we sought to investigate specific genes and mechanisms required for normal basal to luminal cell differentiation. Utilizing human prostate basal epithelial cells and an in vitro differentiation model, we tested the hypothesis that regulation of NOTCH3 by the p38 MAPK family (hereafter p38-MAPK), via MYC, is required for luminal differentiation. Inhibition (SB202190 and BIRB796) or knockdown of p38a (also known as MAPK14) and/or p38d (also known as MAPK13) prevented proper differentiation. Additionally, treatment with a gamma-secretase inhibitor (RO4929097) or knockdown of NOTCH1 and/or NOTCH3 greatly impaired differentiation and caused luminal cell death. Constitutive p38-MAPK activation through MKK6(CA) increased NOTCH3 (but not NOTCH1) mRNA and protein levels, which was diminished upon MYC inhibition (10058-F4 and JQ1) or knockdown. Furthermore, we validated two NOTCH3 enhancer elements through a combination of enhancer (e) RNA detection (BruUV-seq) and luciferase reporter assays. Finally, we found that the NOTCH3 mRNA half-life increased during differentiation or upon acute p38-MAPK activation. These results reveal a new connection between p38-MAPK, MYC and NOTCH signaling, demonstrate two mechanisms of NOTCH3 regulation and provide evidence for NOTCH3 involvement in prostate luminal cell differentiation.
Note12 month embargo; Published online June 1, 2017.
VersionFinal published version
SponsorsU.S. Department of Defense Prostate Cancer Research Program [W81XWH-14-1-0479]; Association for International Cancer Research (Worldwide Cancer Research) [11-0082]; Van Andel Research Institute; University of Arizona