c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis

TY - JOUR

T1 - c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis

AU - Gebhardt, Christoffer

AU - Breitenbach, Ute

AU - Richter, Karl Hartmut

AU - Fürstenberger, Gerhard

AU - Mauch, Cornelia

AU - Angel, Peter

AU - Hess, Jochen

PY - 2005/7

Y1 - 2005/7

N2 - Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.

AB - Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.

KW - Animals

KW - Blotting, Northern

KW - Blotting, Western

KW - Carcinogens

KW - Cell Transformation, Neoplastic

KW - Cells, Cultured

KW - Electrophoretic Mobility Shift Assay

KW - Female

KW - Fibroblasts

KW - Fluorescent Antibody Technique

KW - Humans

KW - In Situ Hybridization

KW - Keratinocytes

KW - Mice

KW - Mice, Transgenic

KW - Promoter Regions, Genetic

KW - Proto-Oncogene Proteins c-fos

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Skin Neoplasms

KW - Tetradecanoylphorbol Acetate

KW - rab GTP-Binding Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/S0002-9440(10)62969-0

DO - 10.1016/S0002-9440(10)62969-0

M3 - SCORING: Journal article

C2 - 15972968

VL - 167

SP - 243

EP - 253

JO - AM J PATHOL

JF - AM J PATHOL

SN - 0002-9440

IS - 1

ER -