title: TGF alpha and v-fos cooperation in transgenic mouse epidermis induces aberrant keratinocyte differentiation and stable, autonomous papillomas.
abstract: To assess the synergistic effect of growth and transcription factor deregulation on carcinogenesis in vivo, mating experiments were performed between transgenic mice expressing human TGF alpha or v-fos exclusively in the epidermis by means of a human keratin K1-based targeting vector (HK1.fos, HK1.TGF alpha and HK1.fos/alpha). While HK1.TGF alpha mice exhibited mild epidermal hyperplasia resulting in a wrinkled appearance, this hyperplasia was significantly increased in HK1.fos/alpha mice which also exhibited a novel opalescent and peeling skin phenotype. HK1.fos/alpha keratinocyte differentiation was considerably deregulated with cornified cells appearing in the granular layer, granular cells in the spinous layer and a sixfold increase in BrdU labeling over normal. In addition, hyperplastic HK1.fos/alpha epidermis exhibited aberrant loricrin, filaggrin and novel K13 expression associated with v-fos expression. Unlike adult HK1.TGF alpha controls, hyperplasia persisted in HK1.fos/alpha adults which also rapidly developed autonomous squamous cell papillomas. These results demonstrate that v-fos and TGF alpha over-expression can cooperate to reprogram keratinocyte differentiation and elicit the early stages of neoplasia. Moreover, TGF alpha over-expression appeared to play an early, initiating role in HK1.fos/alpha papilloma etiology, and a promotion role in the accelerated appearance of v-fos wound-associated preneoplastic phenotypes. However, the stable persistence of HK1.fos/alpha papillomas for up to 12 months, suggests that additional events are required for malignant conversion.
authors.affiliation: Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: X J
authors.initials: XJ
authors.lastname: Wang
authors.forename: D A
authors.initials: DA
authors.lastname: Greenhalgh
authors.forename: X R
authors.initials: XR
authors.lastname: Lu
authors.forename: J R
authors.initials: JR
authors.lastname: Bickenbach
authors.forename: D R
authors.initials: DR
authors.lastname: Roop
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D000091344:Filaggrin Proteins; D005822:Genetic Vectors; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016761:Oncogene Proteins v-fos / Q000502:physiology*; D010212:Papilloma / Q000235:genetics* / Q000473:pathology; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000502:physiology*
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D016761:Oncogene Proteins v-fos; D016211:Transforming Growth Factor alpha; D007633:Keratins