Splicing factor SRSF6 promotes hyperplasia of sensitized skin.
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.
1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2].
Mads A
MA
Jensen
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
John E
JE
Wilkinson
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Adrian R
AR
Krainer
D017398:Alternative Splicing; D000818:Animals; D049109:Cell Proliferation; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000068103:Serine-Arginine Splicing Factors; D012867:Skin / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics
C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; C489470:SRSF6 protein, human; D000068103:Serine-Arginine Splicing Factors