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Nat Struct Mol Biol. 2014 Feb;21(2):189-97. doi: 10.1038/nsmb.2756. Epub 2014 Jan 19.

Splicing factor SRSF6 promotes hyperplasia of sensitized skin.

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1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2].
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.


Many biological processes involve gene-expression regulation by alternative splicing. Here, we identify the splicing factor SRSF6 as a regulator of wound healing and tissue homeostasis in skin. We show that SRSF6 is a proto-oncogene frequently overexpressed in human skin cancer. Overexpressing it in transgenic mice induces hyperplasia of sensitized skin and promotes aberrant alternative splicing. We identify 139 SRSF6-target genes in skin and show that this SR-rich protein binds to alternative exons in the pre-mRNA of the extracellular-matrix protein tenascin C, thus promoting the expression of isoforms characteristic of invasive and metastatic cancer independently of cell type. SRSF6 overexpression additionally results in depletion of LGR6+ stem cells and excessive keratinocyte proliferation and response to injury. Furthermore, the effects of SRSF6 in wound healing assayed in vitro depend on the tenascin-C isoforms. Thus, abnormal SR-protein expression can perturb tissue homeostasis.

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