The Ets dominant repressor En/Erm enhances intestinal epithelial tumorigenesis in ApcMin mice

<p>Abstract</p> <p>Background</p> <p>Ets transcription factors have been widely implicated in the control of tumorigenesis, with most studies suggesting tumor-promoting roles. However, few studies have examined Ets tumorigenesis-modifying functions <it>in vivo </it>using model genetic systems.</p> <p>Methods</p> <p>Using mice expressing a previously characterized Ets dominant repressor transgene in the intestinal epithelium (Villin-En/Erm), we examined the consequences of blocking endogenous Ets-mediated transcriptional activation on tumorigenesis in the Apc^Minmodel of intestinal carcinoma.</p> <p>Results</p> <p>En/Erm expression in the intestine, at levels not associated with overt crypt-villus dysmorphogenesis, results in a marked increase in tumor number in Apc^Minanimals. Moreover, when examined histologically, tumors from En/Erm-expressing animals show a trend toward greater stromal invasiveness. Detailed analysis of crypt-villus homeostasis in these En/Erm transgenic animals suggests increased epithelial turnover as one possible mechanism for the enhanced tumorigenesis.</p> <p>Conclusion</p> <p>Our findings provide <it>in vivo </it>evidence for a tumor-restricting function of endogenous Ets factors in the intestinal epithelium.</p

Synthesis and metal(II) ion complexation of pyridine-2, 6-diamides incorporating amino alcohols

Reaction of 2,6-bis(methoxycarbonyl)pyridine with two equivalents of a β-amino alcohol yields pyridine-2,6-diamides C₆H₃N(CONH–CR₁R₂–CHR₃–OH)₂ [(1) R₁ = R₂ = R₃ = H; (2) R₁ = R₂ = H, R₃ = CH₃; (3) R₁ = CH₃, R2 = R₃ = H; (4) R₁ = C₂H₅, R₂ = R₃ = H; (5) R₁ = C₆H₅CH₂, R₂ = R₃ = H; (6) R₁ = O₂NC₆H₄CH(OH), R₂ = R₃ = H; (7) R₁ = R₂ = CH₃, R₃=H] incorporating the amino alcohols, several of which are chiral, whereas the free diamide ligands show no capacity toward deprotonation up to pH > 12. In the presence of metal(II) ions they undergo concomitant deprotonation and complexation to form [M(L-2H)] compounds. Formation constants have been determined for Cu(II), Ni(II), and Zn(II) complexes of the suite of ligands. Determined values for the two observed steps of log β ML-2H and log β ML-3H (where additional alcohol or coordinated water deprotonation occurs) are approximately −10 and −20, respectively. As pKa values of the diamide cannot be determined independently, absolute log KML-2H values for the di-deprotonated complexes cannot be definitively assigned, although estimates are made using predicted pKa values for the diamide. The circular dichroism spectra of optically active complexes were determined and are discussed