Regulation of Cell Cycle by E2F1 in Primary Cells

Lomazzi, Marina (2004). Regulation of Cell Cycle by E2F1 in Primary Cells. PhD thesis The Open University.



Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer, and in the absence of other genetic alterations, results in lack of differentiation, hyperproliferation and apoptosis. pRB acts as a transcriptional repressor by targeting the E2F transcription factors whose functions are required for S phase entry.

Increased E2F activity can induce S phase in quiescent cells and this fact is a central element of most models for the development of cancer. I provide evidence that E2F1 alone is not sufficient to induce S phase in diploid mouse and human fibroblasts. However, increased E2F1 activity can result in S phase entry in diploid fibroblasts in which the p53-mediated Gl checkpoint is suppressed. Furthermore, I show that E2F1 can induce S phase in primary mouse fibroblasts lacking pRB. These results demonstrate that in addition to working as an E2F-dependent transcriptional repressor, pRB is also required for retaining the Gl checkpoint in response to unprogrammed proliferative signals.

The role of E2F in cell proliferation is not completely understood because it is not known if the E2Fs mainly function as transcriptional repressors or activators. E2Fs need dimerisation with a DP protein to give rise to functional E2F activity and to regulate promoters containing E2F binding sites. I inactivated endogenous DP in tissue culture by RNA interference providing evidence that loss of DPI abrogates E2F DNA binding activity. DP is required for tumour and normal cell growth. In addition, the expression of E2F target genes is severely impaired. These results define a crucial role for DPI in cell proliferation.

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