Increased susceptibility of Sf1(+/-) mice to azoxymethane-induced colon tumorigenesis.

Abstract

Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor-4 nuclear complex has been considered crucial for the initiation of colorectal carcinogenesis. We previously identified splicing factor-1 (SF1) as a novel component of the beta-catenin and T-cell factor-4 complex, and showed that the overexpression of SF1 inhibited the gene transactivational activity of the complex and markedly suppressed beta-catenin-evoked colony formation by human embryonic kidney 293 cells. However, the involvement of SF1 in the process of carcinogenesis in vivo remains unclear. In the present study, we established SF1-knockout mice using the gene trapping method. Homozygous mice (Sf1(-/-)) died during embryonic development before embryonic day (E)8.5, whereas heterozygous (Sf1(+/-)) mice were born alive and developed normally. Azoxymethane (AOM) was given at a dose of 10 mg/kg body weight once a week for 6 weeks to 7-week-old Sf1(+/-) and Sf1(+/+) mice. At 23 weeks after the start of AOM the average number (5.5 +/- 0.6 versus 2.2 +/- 0.2 in females [P = 0.003, Mann-Whitney U-test], 3.7 +/- 0.2 versus 1.7 +/- 0.7 in males [P = 0.014]) and volume of colon tumors per mouse (8.7 +/- 1.6 versus 2.2 +/- 0.5 mm(3) per female [P = 0.0008], 11.3 +/- 3.4 versus 0.6 +/- 0.2 mm(3) per male [P = 0.001]) were significantly higher in Sf1(+/-) than in Sf1(+/+) mice. The increased susceptibility of Sf1(+/-) mice to AOM-induced colon tumorigenesis indicates the crucial involvement of SF1 in the beta-catenin-mediated regulation of proliferation and differentiation of intestinal epithelial cells.

• Authors: Miki Shitashige, Reiko Satow, Kazufumi Honda, Masaya Ono, Setsuo Hirohashi, Tesshi Yamada
• Journal: Cancer science (Cancer Sci) Vol. 98 Issue 12 Pg. 1862-7 (Dec 2007) ISSN: 1349-7006 [Electronic] England
• PMID: 17900258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• DNA-Binding Proteins
• Homeodomain Proteins
• Nerve Tissue Proteins
• RNA Splicing Factors
• Sf1 protein, mouse
• Transcription Factors
• beta Catenin
• engrailed 2 protein
• Azoxymethane

Topics

• Animals
• Azoxymethane (toxicity)
• Colonic Neoplasms (chemically induced, genetics)
• DNA Primers
• DNA-Binding Proteins (deficiency, genetics)
• Disease Models, Animal
• Genes, Lethal
• Genetic Predisposition to Disease
• Genotype
• Homeodomain Proteins (genetics)
• Introns
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (genetics)
• RNA Splicing Factors
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (deficiency, genetics)
• Transcriptional Activation
• beta Catenin (physiology)