title: Structural and biochemical changes underlying a keratoderma-like phenotype in mice lacking suprabasal AP1 transcription factor function.
abstract: Epidermal keratinocyte differentiation on the body surface is a carefully choreographed process that leads to assembly of a barrier that is essential for life. Perturbation of keratinocyte differentiation leads to disease. Activator protein 1 (AP1) transcription factors are key controllers of this process. We have shown that inhibiting AP1 transcription factor activity in the suprabasal murine epidermis, by expression of dominant-negative c-jun (TAM67), produces a phenotype type that resembles human keratoderma. However, little is understood regarding the structural and molecular changes that drive this phenotype. In the present study we show that TAM67-positive epidermis displays altered cornified envelope, filaggrin-type keratohyalin granule, keratin filament, desmosome formation and lamellar body secretion leading to reduced barrier integrity. To understand the molecular changes underlying this process, we performed proteomic and RNA array analysis. Proteomic study of the corneocyte cross-linked proteome reveals a reduction in incorporation of cutaneous keratins, filaggrin, filaggrin2, late cornified envelope precursor proteins, hair keratins and hair keratin-associated proteins. This is coupled with increased incorporation of desmosome linker, small proline-rich, S100, transglutaminase and inflammation-associated proteins. Incorporation of most cutaneous keratins (Krt1, Krt5 and Krt10) is reduced, but incorporation of hyperproliferation-associated epidermal keratins (Krt6a, Krt6b and Krt16) is increased. RNA array analysis reveals reduced expression of mRNA encoding differentiation-associated cutaneous keratins, hair keratins and associated proteins, late cornified envelope precursors and filaggrin-related proteins; and increased expression of mRNA encoding small proline-rich proteins, protease inhibitors (serpins), S100 proteins, defensins and hyperproliferation-associated keratins. These findings suggest that AP1 factor inactivation in the suprabasal epidermal layers reduces expression of AP1 factor-responsive genes expressed in late differentiation and is associated with a compensatory increase in expression of early differentiation genes.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Rorke
authors.affiliation: Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Young
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, CA, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Rice
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, San Francisco and Department of Dermatology, University of California, San Francisco, CA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, San Francisco and Department of Dermatology, University of California, San Francisco, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Crumrine
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, San Francisco and Department of Dermatology, University of California, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Meyer
authors.affiliation: The R.O. Perelman Department of Dermatology, Department of Biochemistry and Molecular Pharmacology, New York University Cancer Institute, New York City, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Blumenberg
authors.affiliation: 1] Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA [2] Dermatology, University of Maryland School of Medicine, Baltimore, MD, USA [3] Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, MD, USA [4] Greenebaum Cancer Center University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000648:ultrastructure; D005260:Female; D000091344:Filaggrin Proteins; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism
chemical_list: D051697:Activating Transcription Factor 1; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D007633:Keratins