Implication of transcription factor E2F in regulation of DNA replication

Abstract

The transcription factor E2F plays crucial roles in induction of S phase in mammalian cells by regulating the expression of genes that encode molecules involved in cell cycle progression. E2F exerts a repressive effect on E2F-responsive genes in G0/G1 phase by associating with the retinoblastoma tumor suppressor gene product pRb and the related protein p130. This repression is relieved by phosphorylation of the pRb family proteins by G1 cyclin (cyclin D and cyclin E) -dependent kinases, resulting in expression of E2F-responsive genes in late G1 with a peak at the G1/S boundary. One group of genes influenced by E2F encode cell cycle regulatory molecules, including members of the E2F family and cyclin E, demonstrating a loop-type regulation of activities of E2F and cyclin E-dependent kinase at this stage in the cell cycle. Another group is involved in DNA replication, including genes for molecules regulating initiation of DNA replication. Overexpression of E2F is sufficient to induce DNA synthesis in serum starved fibroblasts. In addition, overexpression of cyclin E, which is essential for entry into S phase, overcomes G1 arrest caused by inhibition of E2F activity without resuming E2F mediated transcription, suggesting the mergence of the two pathways. Thus, E2F target-gene products and cyclin E-dependent kinase activity apparently co-operate to initiate replication of DNA.

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

“…The E 2 -induced expression profile of E2F1 , a key transcriptional regulator of DNA replication genes (Ohtani 1999), closely parallels the induction of the chromosome replication genes (Figure 6B), consistent with the proposal that E2F1 regulates the expression of components of the DNA replication fork in human breast cancer cell lines exposed to E 2 (Lobenhofer et al 2002). Our data indicate that release from quiescence also involves the E 2 -induced down-regulation of genes that maintain cells in a growth-arrested state ( KIP1 , CCNG2, CCNG1 ).…”

Molecular interaction maps as information organizers and simulation guides

“…This system has been studied extensively in mammalian cells and has yielded confusing experimental results regarding the conditions under which E2F can either stimulate or inhibit its target genes. [20][21][22][23] This scheme covers part of the previously presented network map, 1 but adds recent findings about acetylations. 24 The representation of the promoters and transcript in Fig.…”

The Cell Cycle Regulator Phosphorylated Retinoblastoma Protein Is Associated With Tau Pathology in Several Tauopathies

“…pRb is considered to be a potent tumor suppressor that exerts control of the cell cycle at the G 1 -to-S phase checkpoint by inhibiting the E2F family transcription factors thereby impeding the transcription of genes necessary for transition to S phase (2, 3). Importantly, the fluctuating phosphorylation status of pRb at each of its 16 potential phosphorylation sites determines its function (4); hypophosphorylated pRb intimately associates with E2F thus inhibiting cell cycle progression.…”