Regulation of the G1/S transition phase in mesangial cells by E2F1.
It has been established that E2F transcription factors are essential for the regulation of the cell cycle. The E2Fs play an important role in G1/S transition phase, as they regulate the activation of several genes whose products are required for DNA synthesis. E2Fs bind to the retinoblastoma protein family and their transcriptional activities are suppressed in the G0 and early G1 phases. The E2F family consists of a group of five closely related proteins (E2F1 through E2F5). Proliferation of the mesangial cell is a common feature of many glomerular diseases, but the regulation of mesangial cell cycle has not been clarified, nor has the participation of the E2F family in mesangial cells. To elucidate the mechanisms of G1/S transition phase in mesangial cells, we investigated the roles of the E2F family in the mesangial cell cycle. In primary cultured mesangial cells, the protein expression of E2F1 through E2F3 was induced by fetal calf serum (FCS) stimulation. E2F1 especially was strongly induced by mitogenic stimulation. The E2F4 protein was abundantly expressed in the quiescent state and was slightly increased by FCS stimulation. We considered E2F1 to be representative of the E2F family, and used adenovirus-mediated gene transfer to investigate the function of E2F1 to show that overexpression of E2F1 promoted cell cycle progression as measured by a flow cytometer. Furthermore, we investigated the effect of E2F1 overexpression to cyclin D1 and cyclin E expression. Because we previously reported that the regulation of G1 cyclins is a key factor in the G1/S transition phase in mesangial cells, we showed that overexpression of E2F1 induced protein expression of cyclin D1 and cyclin E and increased promoter activity. Thus, we conclude that E2F1 plays an important role in the G1/S transition phase and acts on the mesangial cell cycle through two distinct pathways: (1) E2F1 directly transcribes an S-phase gene, and (2) E2F1 promotes cell cycle progression via the induction of cyclin D1 and cyclin E.
Inoshita
S
S
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Terada
Y
Y
Nakashima
O
O
Kuwahara
M
M
Sasaki
S
S
Marumo
F
F
D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D050700:E2F5 Transcription Factor; D016193:G1 Phase / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology*; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D050700:E2F5 Transcription Factor; D056465:Retinoblastoma-Binding Protein 1; D014157:Transcription Factors