Expression of the human Cathepsin L inhibitor hurpin in mice: skin alterations and increased carcinogenesis.
The serine protease inhibitor (serpin) hurpin (serpin B13) is a cross class-specific inhibitor of the cysteine protease Cathepsin (Cat) L. Cat L is involved in lysosomal protein degradation, hair follicle morphogenesis, epidermal differentiation and epitope generation of antigens. Hurpin is a 44 kDa protein which is expressed predominantly in epidermal cells. In psoriatic skin samples, hurpin was strongly overexpressed when compared with normal skin. Keratinocytes overexpressing hurpin showed increased resistance towards UVB-induced apoptosis. To further analyse the functional importance of this inhibitor, we have generated transgenic mice with deregulated Cat L activity by expressing human hurpin in addition to the endogenous mouse inhibitor. The three independent transgenic lines generated were characterized by identical effects excluding insertional phenotypes. Macroscopically, mice expressing human hurpin are characterized by abnormal abdominal fur. The number of apoptotic cells and caspase-3 positive cells was reduced after UV-irradiation in transgenic animals compared with wild-type mice. Interestingly, after chemical carcinogenesis, transgenic mice showed an increased susceptibility to develop skin cancer. Array analysis of gene expression revealed distinct differences between wild-type and hurpin-transgenic mice. Among others, differentially expressed genes are related to antigen presentation and angiogenesis. These results suggest an important role of Cat L regulation by hurpin which might be of clinical relevance in human skin diseases.
Walz
Markus
M
Department of Dermatology, Heinrich-Heine-University, Moorenstrasse 5, Düsseldorf, Germany. Markus.Walz@googlemail.com
Kellermann
Sabine
S
Bylaite
Matilda
M
Andrée
Birgit
B
Rüther
Ulrich
U
Paus
Ralf
R
Kloepper
Jennifer E
JE
Reifenberger
Julia
J
Ruzicka
Thomas
T
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002273:Carcinogens; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003546:Cysteine Endopeptidases; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate; D014466:Ultraviolet Rays / Q000009:adverse effects
D002273:Carcinogens; C530652:SERPINB13 protein, human; C530653:Serpinb13 protein, mouse; D015843:Serpins; D015127:9,10-Dimethyl-1,2-benzanthracene; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D013755:Tetradecanoylphorbol Acetate