Format

Send to

Choose Destination
Mol Cancer Res. 2015 Aug;13(8):1185-96. doi: 10.1158/1541-7786.MCR-15-0014. Epub 2015 May 1.

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis.

Author information

1
Sir Peter MacCallum Oncology Department, Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. University of Melbourne, Melbourne, Victoria, Australia. Latrobe Institute of Molecular Science, Department of Genetics, Latrobe University, Bundoora, Victoria, Australia. Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
2
Sir Peter MacCallum Oncology Department, Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. University of Melbourne, Melbourne, Victoria, Australia.
3
Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
4
Sir Peter MacCallum Oncology Department, Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. University of Melbourne, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
5
Sir Peter MacCallum Oncology Department, Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. University of Melbourne, Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia. rob.ramsay@petermac.org.

Abstract

Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (Myb(Plt4)) 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, Myb(Plt4) 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. Myb(Plt4/Plt4) mice died prematurely on an Apc(Min/) (+) background associated with hematopoietic defects, including a myelodysplasia; nevertheless, Apc(Min/) (+) mice were protected from intestinal tumorigenesis when crossed to Myb(Plt4/) (+) 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.

PMID:
25934694
DOI:
10.1158/1541-7786.MCR-15-0014
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center