Hepsin regulates TGFβ signaling via fibronectin proteolysis.
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ABSTRACT:
SUBMITTER: Belitskin D
PROVIDER: S-EPMC8567232 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To test if ectopic overexpression of hepsin (TMPRSS1) induces TGFβ signaling in the context of tumorigenesis, we made use of a previously published tumor syngraft model of Myc-driven breast cancer (Partanen et al., 2012 PMID: 22308451). Wap-Myc mammary tumor cells, which express high Myc levels, were isolated from donor mice, transduced with the pIND21-HPN lentiviral construct that allows doxycycline (DOX)-induced hepsin overexpression, and subsequentially transplanted into recipient mice. Consistent with the notion that hepsin promotes TGFβ signaling, western blot analysis revealed increased phospho-Smad2/3 and upregulation of the TGFβ signaling downstream target SNAIL in Wap-Myc tumors with DOX-induced hepsin overexpression compared to control (-DOX) tumors. RNAseq analysis of these tumors provided additional evidence for TGFβ pathway upregulation by hepsin as the most significantly upregulated gene signatures corresponded to the TGFβ signaling pathway. The largest cluster of gene signatures affected by hepsin overexpression, however, was related to the ECM and integrins.
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2014-07-11 | E-GEOD-59272 | biostudies-arrayexpress
Project description:BackgroundSebaceous glands are components of the skin essential for its normal lubrication by the production of sebum. This contributes to skin health and more importantly is crucial for the skin barrier function. A mechanistic understanding of sebaceous gland cells growth and differentiation has lagged behind that for keratinocytes, partly because of a lack of an in vitro model that can be used for experimental manipulation.MethodsWe have developed an in vitro culture model to isolate and grow primary human sebocytes without transformation that display functional characteristics of sebocytes. We used this novel method to probe the effect of Transforming Growth Factor β (TGFβ) signaling on sebocyte differentiation, by examining the expression of genes involved in lipogenesis upon treatment with TGFβ1. We also repressed TGFβ signaling through knockdown of the TGFβ Receptor II to address if the effect of TGFβ activation is mediated via canonical Smad signal transduction.ResultsWe find that activation of the TGFβ signaling pathway is necessary and sufficient for maintaining sebocytes in an undifferentiated state. The presence of TGFβ ligand triggered decreased expression in genes required for the production of characteristics sebaceous lipids and for sebocyte differentiation such as FADS2 and PPARγ, thereby decreasing lipid accumulation through the TGFβ RII-Smad2 dependent pathway.ConclusionTGFβ signaling plays an essential role in sebaceous gland regulation by maintaining sebocytes in an undifferentiated state. This data was generated using a novel method for human sebocyte culture, which is likely to prove generally useful in investigations of sebaceous gland growth and differentiation. These findings open a new paradigm in human skin biology with important implications for skin therapies.
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