Nature Genetics31, 190 - 194 (2002)
Published online: 6 May 2002; | doi:10.1038/ng891
Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry
Marina Lomazzi1, M. Cristina Moroni1, Michael R. Jensen1, 2, Emanuela Frittoli1
& Kristian Helin1, 2
1
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
2
The FIRC Institute for Molecular Oncology, Milan, Italy.
Correspondence should be addressed to Kristian Helin khelin@ieo.it
Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer1. In the absence of other genetic alterations, this deregulation results in lack of differentiation, hyperproliferation and apoptosis2. The pRB protein acts as a transcriptional repressor by targeting the E2F transcription factors, whose functions are required for entry into S phase3,
4. Increased E2F activity can induce S phase in quiescent cells—this is a central element of most models for the development of cancer1,
3,
4. 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.
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