Faculty Collaboration Database

A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice. Cancer Prev Res (Phila) 2010 Sep;3(9):1148-56

Date

08/19/2010

Pubmed ID

20716630

Pubmed Central ID

PMC2933283

DOI

10.1158/1940-6207.CAPR-10-0023

Scopus ID

2-s2.0-77956408222 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

Lung cancer is the leading cause of cancer mortality in the United States and worldwide. The identification of key regulatory and molecular mechanisms involved in lung tumorigenesis is therefore critical to increase our understanding of this disease and could ultimately lead to targeted therapies to improve prevention and treatment. Induction of members of the activator protein-1 (AP-1) transcription factor family has been described in human non-small cell lung carcinoma. Activation of AP-1 can either stimulate or repress transcription of multiple gene targets, ultimately leading to increased cell proliferation and inhibition of apoptosis. In the present study, we show induction of AP-1 in carcinogen-induced mouse lung tumors compared with surrounding normal lung tissue. We then used a transgenic mouse model directing conditional expression of the dominant-negative c-jun mutant TAM67 in lung epithelial cells to determine the effect of AP-1 inhibition on mouse lung tumorigenesis. Consistent with low AP-1 activity in normal lung tissue, TAM67 expression had no observed effects in adult mouse lung. TAM67 decreased tumor number and overall lung tumor burden in chemically induced mouse lung tumor models. The most significant inhibitory effect was observed on carcinoma burden compared with lower-grade lesions. Our results support the concept that AP-1 is a key regulator of mouse lung tumorigenesis, and identify AP-1-dependent transcription as a potential target to prevent lung tumor progression.

Author List

Tichelaar JW, Yan Y, Tan Q, Wang Y, Estensen RD, Young MR, Colburn NH, Yin H, Goodin C, Anderson MW, You M

MESH terms used to index this publication - Major topics in bold

Animals
Benzo(a)pyrene
Carcinogens
Carcinoma
Cell Transformation, Neoplastic
Cytoprotection
Down-Regulation
Gene Expression Regulation, Neoplastic
Genes, Dominant
Genes, Tumor Suppressor
Genes, jun
Lung Neoplasms
Mice
Mice, Transgenic
Mutant Proteins
Peptide Fragments
Proto-Oncogene Proteins c-jun
Transcription Factor AP-1