Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry.
Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer. In the absence of other genetic alterations, this deregulation results in lack of differentiation, hyperproliferation and apoptosis. The pRB protein acts as a transcriptional repressor by targeting the E2F transcription factors, whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells--this is a central element of most models for the development of cancer. We show that although E2F1 alone is not sufficient to induce S phase in diploid mouse and human fibroblasts, increased E2F1 activity can result in S-phase entry in diploid fibroblasts in which the p53-mediated G1 checkpoint is suppressed. In addition, we show that E2F1 can induce S phase in primary mouse fibroblasts lacking pRB. These results indicate that, in addition to acting as an E2F-dependent transcriptional repressor, pRB is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals.
Lomazzi
Marina
M
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
Moroni
M Cristina
MC
Jensen
Michael R
MR
Frittoli
Emanuela
E
Helin
Kristian
K
D000818:Animals; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016193:G1 Phase / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D016160:Retinoblastoma Protein / Q000502:physiology*; D016196:S Phase / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53