Defective Myb function ablates Cyclin E1 expression and perturbs intestinal carcinogenesis

Dane Cheasley, Lloyd Pereira, Shienny Sampurno, Oliver Sieber, Robert Jorissen, Huiling Xu, Markus Germann, Yan Yuqian, Robert G. Ramsay, Jordane Malaterre

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (MybPlt4) were examined, it was noted that Cyclin E1 (Ccne1) expression was reduced. Furthermore, the induction of Ccne1 in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated Ccne1 and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1-driven tumor growth. Here, it was found that Myb/MYB and Ccne1/CCNE1 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 Ccne1 promoter and regulated its endogenous expression. In contrast, MybPlt4 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. MybPlt4/Plt4 mice died prematurely on an ApcMin/+ background associated with hematopoietic defects, including a myelodysplasia; nevertheless, ApcMin/+ mice were protected from intestinal tumorigenesis when crossed to MybPlt4/+ mice. Knockdown of CCNE1 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. Implications: This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis.

Original languageEnglish
Pages (from-to)1185-1196
Number of pages12
JournalMolecular Cancer Research
Volume13
Issue number8
DOIs
Publication statusPublished - 1 Aug 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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