Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profile associated with the PDZ ligand-motif of HPV16-E6 oncoprotin in the skin of transgenic mice models

ABSTRACT: The K14E6 transgenic mice developskin hyperplasia,benign tumors and skin cancer. The tumor formation capacity diminishes when E6 lacks its PDZ ligand-motif. This study aims to compare the transciptional profiles of transgenic K14E6 mice with K14E6 Δ146-151 (lacking the PDZ domain) in order to explore the role of PDZ in early skin carcinogenesis. Skin tissue from three different strains of mice were dissected for RNA extraction, processing and hybridization in Affymetrix Mouse Genome 430 2,0 array. We processed three biological replicates per strain. 3 mice were used for each replicate pool for a final RNA concentration of 3 micrograms. The arrays were analyzed using Partek Genomics suite software.

ORGANISM(S): Mus musculus

SUBMITTER: Laura Uribe

PROVIDER: E-GEOD-22417 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.

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Gene expression profile associated with the PDZ ligand-motif of HPV16-E6 oncoprotin in the skin of transgenic mice models

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