Splicing factor SRSF6 promotes hyperplasia of sensitized skin

  • Nat Struct Mol Biol. 2014 Feb;21(2):189-97. doi: 10.1038/nsmb.2756.
Mads A Jensen  1 ,  John E Wilkinson  2 ,  Adrian R Krainer  3
Affiliations
  • 1. 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2].
  • 2. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 3. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
PMID: 24440982 DOI: 10.1038/nsmb.2756
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.