title: RIP4 regulates epidermal differentiation and cutaneous inflammation.
abstract: The receptor-interacting protein (RIP) family kinase RIP4 interacts with protein kinase C (PKC) isoforms and is implicated in PKC-dependent signaling pathways. RIP4(-/-) mice die at birth with epidermal differentiation defects, causing fusions of all external orifices and loss of the esophageal lumen. To further understand RIP4 function in the skin, we generated transgenic mice with epidermal-specific expression of RIP4 using the human keratin-14 promoter (K14-RIP4). The K14-RIP4 transgene rescued the epidermal phenotype of RIP4(-/-) mice, showing that RIP4 acts autonomously in the epidermis to regulate differentiation. Although RIP4(-/-) mice share many phenotypic similarities with inhibitor kappaB kinase (IKK)alpha(-/-) mice and stratifin repeated epilation (Sfn(Er/Er)) mice, the K14-RIP4 transgene failed to promote epidermal differentiation in these mutant backgrounds. Unexpectedly, topical treatment of K14-RIP4 mice with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced dramatic, neutrophilic inflammation, an effect that was independent of tumor necrosis factor type 1 receptor (TNFR1/p55) function. Despite their enhanced sensitivity to TPA, K14-RIP4 mice did not have an altered frequency of tumor formation in TPA-promoted skin cancer initiated with 7,12-dimethylbenz[a]anthracene (DMBA). These data suggest that RIP4 functions in the epidermis through PKC-specific signaling pathways to regulate differentiation and inflammation.
authors.affiliation: Department of Oncology, Amgen, Seattle, Washington, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Rountree
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Willis
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.forename: Hal
authors.initials: H
authors.lastname: Blumberg
authors.forename: Keith
authors.initials: K
authors.lastname: Bailey
authors.forename: Charles
authors.initials: C
authors.lastname: Dean
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Peschon
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Holland
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002454:Cell Differentiation / Q000502:physiology; D003877:Dermatitis, Contact / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D004817:Epidermis / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D053547:Keratin-14 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D048948:14-3-3 Proteins; D002273:Carcinogens; C507540:KRT14 protein, human; D053547:Keratin-14; D047888:Receptors, Tumor Necrosis Factor, Type I; C499130:Sfn protein, mouse; C506236:Tnfrsf1a protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C430884:Ripk4 protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate