Abstract
165
Aberrant expression of tumor suppressor genes and oncogenes causes cancers and restoring their function is one of the potential therapeutic interventions. Oxidative Stress-induced Growth Inhibitor 1 (OSGIN1), also known as OKL38/BDGI, is a newly characterized tumor suppressor gene and its expression is regulated by oxidative stress, carcinogen, nephrotoxin, immunotoxin, reproductive toxin and heavy metal. To decipher the regulation mechanisms of OSGIN1, the minimal promoter region of this gene is cloned and characterized in this study. Progressive deletion of the OSGIN1 promoter P1 reveals a minimal promoter region from -202 to +5 positions. This minimal promoter is shown to direct high expression of OSGIN1-1a variant in breast, liver and cervical cancer cell lines. Electro-mobility shift assay demonstrates binding of nuclear proteins to several regions within P1. Super-shift and competition assay identify NF1 as the nuclear factor bound to region -194 to -180 within P1. Quantitative PCR and Western blot analysis show that the expression of NF1 is inversely correlated to the transcript expression of OSGIN1-1a variant, which is the major transcript driven by the promoter P1. Attenuating binding of NF1 to promoter P1 via site-directed mutagenesis resulted in an increase in promoter P1 activity. Conversely, overexpression of NF1A, -B, -C and -X in HepG2 cells repressed activity of promoter P1-driven reporter gene construct. This study demonstrates that NF1 is involved in the negative regulation of OSGIN1 and possible role in regulating carcinogenesis and cellular differentiation.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA