Extracellular Signal Regulated Kinase
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E2F Pidder Jansen-DuÈrr Institute for Biomedical Ageing Research, Austrian Academy of Sciences, Innsbruck, Austria [email protected]
Definition Family of transcription factors involved in cellcycle regulated transcription; they control the expression of genes coding for growth regulatory proteins.
quired for DNA binding. E2F/DP heterodimers function as transcriptional regulators of a variety of cellular genes, some of which are involved in cell-cycle checkpoint control. E2F target genes can be grouped as follows: 1. Genes that code for cell-cycle regulators (Fig. 1), such as cyclin E, cyclin A, the retinoblastoma protein, p107 and Ran BP1. Expression of these genes is driven by E2F. E2F thereby directly controls the progression from one cell cycle phase into the other, particularly at the G1/S and the G2/M transition. E2F also activates expression of the p14 (ARF) gene, an upstream regulator of p53. 2. Genes that code for enzymes involved in DNA replication, such as thymidilate synthetase, thymidine kinase, dihydrofolat reductase, etc. It is believed that up-regulation of these genes prepares cells for DNA synthesis which are in the G1 phase of the cellcycle. Cellular and molecular regulation *
Characteristics The E2F family of transcription factors has the five members, E2F-1 to 5, which are capable to either activate or repress transcription, depending on the promoter context and the composition of E2F complexes (see below). A sixth member of the E2F family, referred to as EMA or E2F-6, also binds E2F recognition sites but only acts as a repressor of transcription. Members of the E2F family form heterodimers with members of the DP family. The latter consists of two genes, DP1 and DP2, that encode several isoforms. Heterodimerization is re-
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E2F proteins are regulated by cellular tumor suppressor proteins (Fig. 2). Members of the retinoblastoma protein [! retinoblastoma protein, biological and clinical functions] family (pRB, p107 and p130) associate with the E2F/DP heterodimers, block their transactivation capacity and, in some cases, convert these activators of transcription into transcriptional repressors. The latter convertion appears to involve the tethering of histone deacetylases to E2F/pRB complexes. E2F regulates the activation of the tumor suppressor p53 via p14 (ARF). In turn, E2F function is regulated by p53 via a competition for the p300 coactivator protein.
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E2F
E2F. Fig. 1 ± Control of E2F activity in cancer cells. Signals and regulatory pathways that induce or repress the activity of the E2F/DP transcription factors are indicated. The picture contains only proteins with a known function in human cancer; although other proteins that can modulate E2F/DP activity have been identified their role in cancer is not yet clear. The activity of E2F/DP transcription factors is controlled by chromatin-modifying enzymes such as HDAC-1 and Mi2, which block the transcription of E2F-dependent genes by deacetylating histones. In contrast, histone acetyl transferases such as p300 and P/CAF, act
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