Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

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Version: Final published version
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Serval ID
serval:BIB_BD87C4211151
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.
Journal
Nature Cell Biology
Author(s)
Procopio M.G., Laszlo C., Al Labban D., Kim D.E., Bordignon P., Jo S.H., Goruppi S., Menietti E., Ostano P., Ala U., Provero P., Hoetzenecker W., Neel V., Kilarski W.W., Swartz M.A., Brisken C., Lefort K., Dotto G.P.
ISSN
1476-4679 (Electronic)
ISSN-L
1465-7392
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
17
Number
9
Pages
1193-1204
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.
Keywords
Animals, Carcinoma, Squamous Cell/metabolism, Carcinoma, Squamous Cell/pathology, Cell Aging, Cell Line, Tumor, Down-Regulation, Fibroblasts/physiology, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics, Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism, Mice, Receptors, Fibroblast Growth Factor/metabolism, Signal Transduction, Skin Neoplasms/metabolism, Skin Neoplasms/pathology, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/metabolism
Pubmed
Web of science
Create date
11/09/2015 8:40
Last modification date
20/08/2019 16:31
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