title: Loss of Grainy head-like 1 is associated with disruption of the epidermal barrier and squamous cell carcinoma of the skin.
abstract: The Grainyhead-like 1 (GRHL1) transcription factor regulates the expression of desmosomal cadherin desmoglein 1 (Dsg1) in suprabasal layers of the epidermis. As a consequence, the epidermis of Grhl1-null mice displays fewer desmosomes that are abnormal in structure. These mice also exhibit mild chronic skin barrier defects as evidenced by altered keratinocyte terminal differentiation, increased expression of inflammatory markers and infiltration of the skin by immune cells. Exposure of Grhl1 (-/-) mice to a standard chemical skin carcinogenesis protocol results in development of fewer papillomas than in wild type control animals, but with a rate of conversion to squamous cell carcinoma (SCC) that is strikingly higher than in normal littermates. The underlying molecular mechanism differs from mice with conditional ablation of a closely related Grhl family member, Grhl3, in the skin, which develop SCC due to the loss of expression of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling pathway.
authors.affiliation: Laboratory of Signal Transduction, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Mlacki
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia.
authors.forename: Charbel
authors.initials: C
authors.lastname: Darido
authors.affiliation: Department of Medicine, Monash University Central Clinical School, Prahran, Victoria, Australia ; Alfred Hospital, Prahran, Victoria, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jane
authors.affiliation: Laboratory of Signal Transduction, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wilanowski
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; C528337:Grhl1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene