Splicing factor SRSF6 promotes hyperplasia of sensitized skin

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

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Proliferation
  • Homeostasis / genetics
  • Humans
  • Hyperplasia / genetics
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Serine-Arginine Splicing Factors
  • Skin / pathology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Wound Healing / genetics

Substances

  • Nuclear Proteins
  • Phosphoproteins
  • RNA-Binding Proteins
  • SRSF6 protein, human
  • Serine-Arginine Splicing Factors

Associated data

  • GEO/GSE52458