c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis
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c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis. / Gebhardt, Christoffer; Breitenbach, Ute; Richter, Karl Hartmut; Fürstenberger, Gerhard; Mauch, Cornelia; Angel, Peter; Hess, Jochen.
In: AM J PATHOL, Vol. 167, No. 1, 07.2005, p. 243-53.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -