title: Role of β-TrCP ubiquitin ligase receptor in UVB mediated responses in skin.
abstract: Skin cancers are the most common cancers in the United States. Exposure to UVB radiation is a major risk factor for skin cancer induction. SCF(β-TrCP) E3 ubiquitin ligase has been found to be involved in cell cycle, cell proliferation and transformation. Aberrant up-regulation of beta-transducin repeats-containing proteins (β-TrCP) is often found in cancer cell lines and primary tumors. We have previously demonstrated that β-TrCP2 is over-expressed in chemically induced mouse skin tumors. Various cellular stress stimuli, including UVB, induce an increase in β-TrCP1 mRNA and protein levels in human cells. We have previously shown that inhibition of β-TrCP function, by induction of dominant negative β-TrCP2 (β-TrCP2(ΔF)), in vitro in hTERT immortalized normal keratinocytes, results in increase in UVB induced apoptosis. We have generated transgenic mice with inducible, selective expression of dominant negative β-TrCP2 in epidermis with the Keratin 5 promoter (K5-rTA x TRE-HA-β-TrCP(ΔF)). Here we report that inhibition of β-TrCP function in mouse epidermis results in decrease in UVB-induced edema, hyperplasia, and inflammatory response and increment in UVB-induced apoptosis in skin. Our results suggest that β-TrCP may be an essential player in UVB induced responses in skin and can be a potential therapeutic target for skin cancer.
authors.affiliation: Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. nbhatia@dermatology.wisc.edu
authors.forename: Neehar
authors.initials: N
authors.lastname: Bhatia
authors.forename: Tara A
authors.initials: TA
authors.lastname: Demmer
authors.forename: Alok K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Irina
authors.initials: I
authors.lastname: Elcheva
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Spiegelman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004487:Edema / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D053555:Keratin-5 / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D053555:Keratin-5; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases