Differential roles of E-type cyclins during transformation of murine E2F-1-deficient cells.
Deregulation of retinoblastoma gene product (pRB) is a hallmark of cancer, which acts as a transcriptional repressor by targeting E2F transcription factors. A transcription factor E2F-1 is not only important for S phase entry of cell cycle, but also stimulates gene expression of pro-apoptotic molecules. To investigate roles of E2F-1 and its target genes in cellular transformation, we studied murine E2F-1-deficient embryonic fibroblasts. Compared with control wild-type cells, E2F-1-deficient cells at early passages were less sensitive to exposure to gamma-radiation and showed an increase of colony formation, while their growth was slow. After sequential passages, the growth of E2F-1-deficient cells reached closely to that of wild-type cells. Immunoblot study of E2F target genes showed that multiple passages of E2F-1-deficient cells resulted in preferential increase of cyclin E2 expression. Furthermore, carcinogenicity study using N-nitrosomethylbenzylamine demonstrated that, compared to wild-type mice, fore-stomach tumors in E2F-1-deficient mice expressed an increased amount of cyclin E2, but not cyclin E1. Taken together, the present study shows that differential roles of E-type cyclins are involved at least partially in the process of cellular transformation, supporting the concept of important roles of the E2F regulatory pathway in carcinogenesis.
Ishii
Hideshi
H
Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. hishii@ms.jichi.ac.jp
Mimori
Koshi
K
Yoshikawa
Yasuji
Y
Mori
Masaki
M
Furukawa
Yusuke
Y
Vecchione
Andrea
A
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005347:Fibroblasts / Q000528:radiation effects; D051379:Mice; D008817:Mice, Mutant Strains; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
C503689:Ccne2 protein, mouse; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D014157:Transcription Factors; C014707:nitrosobenzylmethylamine; D004128:Dimethylnitrosamine