Data from Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Abstract

<div>Abstract<p>Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (<i>Myb<sup>Plt4</sup></i>) were examined, it was noted that Cyclin E1 (<i>Ccne1</i>) expression was reduced. Furthermore, the induction of <i>Ccne1</i> in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated <i>Ccne1</i> and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1–driven tumor growth. Here, it was found that <i>Myb</i>/<i>MYB</i> and <i>Ccne1</i>/<i>CCNE1</i> expressions were coupled in both mouse and human adenomas. In addition, the low molecular weight Cyclin E1 was the predominant form in intestinal crypts and adenomatous polyposis coli (Apc)–mutant adenomas. Chromatin immunoprecipitation (ChIP) analysis confirmed that Myb bound directly to the <i>Ccne1</i> promoter and regulated its endogenous expression. In contrast, <i>Myb<sup>Plt4</sup></i> served as a dominant-negative factor that inhibited wild-type Myb and this was not apparently compensated for by the transcription factor E2F1 in intestinal epithelial cells. <i>Myb<sup>Plt4/Plt4</sup></i> mice died prematurely on an <i>Apc<sup>Min/</sup></i><sup>+</sup> background associated with hematopoietic defects, including a myelodysplasia; nevertheless, <i>Apc<sup>Min/</sup></i><sup>+</sup> mice were protected from intestinal tumorigenesis when crossed to <i>Myb<sup>Plt4/</sup></i><sup>+</sup> mice. Knockdown of <i>CCNE1</i> transcript in murine colorectal cancer cells stabilized chromosome ploidy and decreased tumor formation. These data suggest that Cyclin E1 expression is Myb dependent in normal and transformed intestinal epithelial cells, consistent with a cell-cycle progression and chromosome instability role in cancer.</p><p><b>Implications:</b> This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis. <i>Mol Cancer Res; 13(8); 1185–96. ©2015 AACR</i>.</p></div>