The regulation of E2F by pRB-family proteins

Abstract

Much has been written about the functions of the E2F transcription factor and the product of the retinoblastoma tumor suppressor gene (pRB). These proteins have been described in terms that vary from ''master regulators of cell cycle and differentiation'' to ''peripheral factors that lie outside the core cell cycle machinery.'' Most often, pRB and E2F are described in short and simple terms as opposing molecules that control the G 1 -to Sphase transition.There is an element of truth in each of these descriptions. E2F-and pRB-family proteins clearly play important roles in cell proliferation and differentiation. The extent to which they are master regulators or peripheral factors is a question of semantics, and these terms tell us more about the writer than the proteins. Perhaps the most important development in the E2F literature is the appreciation that E2F and pRB are not unique molecules with functions that can be defined in black and white terms. Instead, E2F and pRB represent families of related proteins that have diverse and occasionally contradictory activities. We now know a great deal about E2F complexes and pRB-family proteins and the emerging picture defies a one-line explanation. The fascinating variety of activities ascribed to various E2F complexes challenges us to place these into context and to find the right perspective.This review is presented into two sections. The first section summarizes the tremendous progress into the composition and properties of E2F and the many interactions that coordinately regulate E2F-dependent transcription. The rapid growth in the size of the E2F literature hides the fact that several fundamental questions have not been fully answered. Because of this, the second section of this review details five unresolved issues that have been highlighted by recent publications. It is impossible to cover all of the relevant E2F literature in a single review and readers are referred to reviews by Farnham (1995);Sardet et al. (1997); Helin (1998); and Yamasaki (1998) for a comprehensive survey.

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells

“…The basis of this cell cycle regulation has never been investigated, but our demonstration that E2F1 and E2F3 are able to bind to a consensus site situated in the 5 0 untranslated region of the gene and that a decrease in E2F1 mRNA levels by siRNA or antisense is associated with decreased DDB2 expression proves that E2F regulates the expression of mouse DDB2, at least in hepatocytes. This finding provides for the first time, a plausible mechanism for the cell cycle regulation of expression of DDB2 as upon Rb phosphorylation in G1/S, E2F activity also increases to peak in S phase (for reviews, see Dyson, 1998;Muller and Helin, 2000). Whether E2F transcriptionally regulates DDB2 in other species remains to be confirmed, but the identification of an E2F site downstream of the initiation of transcription site in human DDB2 suggests that this may also be the case in human cells (Nichols et al, 2003).…”

Grape-seed derived procyanidins interfere with adipogenesis of 3T3-L1 cells at the onset of differentiation

“…Unphosphorylated pRb maintains its ability to repress E2F transcriptional activity. 50 The E2F family represents transcription factors that regulate several genes necessary for progression through the cell cycle (recently reviewed in Bracken et al 51 ). Concomitantly to the GSPE upregulation of p21 mRNA, in our microarrays we also observed some of the E2F target genes (and therefore downstream of p21) downregulated due to GSPE treatment, such as cyclin A, cell division control protein 2, DNA topoisomerase II, polo-like kinase (PLK) and other cell cycle-related genes.…”

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

“…In quiescent cells, RB and its related proteins, p107 and p130, associate with the E2F family of transcriptional factors, and repress the expression of E2F-responsive genes involved in the S-phase progression (Dyson, 1998). In response to external mitogenic stimuli, cyclin-dependent kinases (CDKs) are activated and phosphorylate RB protein.…”