Abstract

Project 1 addresses the regulation of keratinocyte differentiation and inflammation and the relationship of these processes to cutaneous cancer initiation. We show that CLIC4, a p53 and c-Myc inducible chloride channel protein, is required for keratinocyte differentiation. During keratinocytes differentiation cytoplasmic CLIC4 translocates to the nucleus through a process involving cysteine nitrosylation, and nuclear CLIC4 induces the expression of differentiation markers. In a second approach we show that protein kinase C (PKC) alpha mediates keratinocyte intraepidermal neutrophilic infiltration through upregulation of ligands for CXCR2, and that receptor on keratinocytes is required for tumor growth. Furthermore, there is synergy between the EGF receptor and cytokines for induction of GM-CSF, a cytokine involved in cutaneous inflammation. Cutaneous inflammation is also mediated by upregulation of S100A15, an EF hand protein that is particularly elevated in psoriasis and certain human cancers. Finally, we report in this project that caloric restriction reduces the number and size of breast cancers induced in rats exposure to chemical carcinogens.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC004504-34
Application #
7337781
Study Section
(LCCT)
Project Start
Project End
Budget Start
Budget End
Support Year
34
Fiscal Year
2006
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Pastore, Saveria; Mascia, Francesca (2008) Novel acquisitions on the immunoprotective roles of the EGF receptor in the skin. Expert Rev Dermatol 3:525-527
Lichti, Ulrike; Anders, Joanna; Yuspa, Stuart H (2008) Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat Protoc 3:799-810
Suh, Kwang S; Mutoh, Michihiro; Mutoh, Tomoko et al. (2007) CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation. J Cell Sci 120:2631-40
Stepp, Mary Ann; Liu, Yueyuan; Pal-Ghosh, Sonali et al. (2007) Reduced migration, altered matrix and enhanced TGFbeta1 signaling are signatures of mouse keratinocytes lacking Sdc1. J Cell Sci 120:2851-63
Wolf, Ronald; Voscopoulos, Christopher J; FitzGerald, Peter C et al. (2006) The mouse S100A15 ortholog parallels genomic organization, structure, gene expression, and protein-processing pattern of the human S100A7/A15 subfamily during epidermal maturation. J Invest Dermatol 126:1600-8
Li, Luowei; Sampat, Keeran; Hu, Nancy et al. (2006) Protein kinase C negatively regulates Akt activity and modifies UVC-induced apoptosis in mouse keratinocytes. J Biol Chem 281:3237-43
Cataisson, Christophe; Pearson, Andrea J; Tsien, Margaret Z et al. (2006) CXCR2 ligands and G-CSF mediate PKCalpha-induced intraepidermal inflammation. J Clin Invest 116:2757-66
Shiio, Yuzuru; Suh, Kwang S; Lee, Hookeun et al. (2006) Quantitative proteomic analysis of myc-induced apoptosis: a direct role for Myc induction of the mitochondrial chloride ion channel, mtCLIC/CLIC4. J Biol Chem 281:2750-6
Boeshans, Karen M; Wolf, Ronald; Voscopoulos, Christopher et al. (2006) Purification, crystallization and preliminary X-ray diffraction of human S100A15. Acta Crystallograph Sect F Struct Biol Cryst Commun 62:467-70
Cataisson, Christophe; Pearson, Andrea J; Torgerson, Sara et al. (2005) Protein kinase C alpha-mediated chemotaxis of neutrophils requires NF-kappa B activity but is independent of TNF alpha signaling in mouse skin in vivo. J Immunol 174:1686-92

Showing the most recent 10 out of 19 publications