E2F4 loss suppresses tumorigenesis in Rb mutant mice

Abstract

The E2F transcription factors mediate the activation or repression of key cell cycle regulatory genes under the control of the retinoblastoma protein (pRB) tumor suppressor and its relatives, p107 and p130. Here we investigate how E2F4, the major "repressive" E2F, contributes to pRB's tumor-suppressive properties. Remarkably, E2F4 loss suppresses the development of both pituitary and thyroid tumors in Rb(+/-) mice. Importantly, E2F4 loss also suppresses the inappropriate gene expression and proliferation of pRB-deficient cells. Biochemical analyses suggest that this tumor suppression occurs via a novel mechanism: E2F4 loss allows p107 and p130 to regulate the pRB-specific, activator E2Fs. We also detect these novel E2F complexes in pRB-deficient cells, suggesting that they play a significant role in the regulation of tumorigenesis in vivo.

Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis

“…It has been demonstrated that E2F transcription factors that normally bind pRb (i.e. E2F1, E2F2, E2F3) may bind p107 in Rb-deficient cells (Lee et al, 2002). Our results support this observation and further indicate that functional compensation in Rb-deficient keratinocytes by p107 crucially depends on the absolute levels of p107 protein.…”

A dynamic switch in Rb+/− mediated neuroendocrine tumorigenesis

“…Furthermore, cooperation occurs between Rb loss and the inactivation of Cip1, Kip1, Arf or Trp53 as judged by shortened survival and increased ILP tumor severity (Williams et al, 1994a;Brugarolas et al, 1998;Park et al, 1999;Tsai et al, 2002), as does cooperation between Ink4c and Kip1 or Cip1 for increased ILP tumor severity and shortened survival (Franklin et al, 1998(Franklin et al, , 2000. In contrast, loss of E2f1 or E2f4 lengthened survival and decreased the penetrance of the ILP tumors (Yamasaki et al, 1998;Lee et al, 2002). More recently, loss of E2f3 has been shown to decrease the severity of the ILP tumors in Rb þ /À mice (Ziebold et al, 2003).…”

“…Previously, we demonstrated that inactivation of E2f1 inhibits neuroendocrine tumorigenesis in Rb þ /À mice by reducing the penetrance and severity of tumors, thereby extending the lifespan of Rb þ /À animals (Yamasaki et al, 1998). Curiously, inactivation of E2F4 also extends the lifespan of Rb þ /À animals by liberating more p107 and p130 to bind E2F family members normally bound by pRB (Lee et al, 2002). Loss of Cip1 (p21) enhances ILP tumorigenesis and shortens the lifespan of Rb þ /À animals (Brugarolas et al, 1998), as does loss of Kip1 (p27) (Park et al, 1999).…”

Pocket proteins and cell cycle control

“…pRB can substitute for p107/p130 in the CERC, and may there by maintain normal regulation in p107/p130-deficient cells (Le Cam et al, 1999). In contrast, it is suggested that p107 and p130 might not substitute for pRB at the E2F-Sp1 element (except under unusual circumstances, Lee et al, 2002), leading to E2F derepression in pRB-deficient as well as in E2F1-3-deficient cells ( further showed that pRB is required for the recruitment of HDAC1 as well as for histone deacetylation within the cyclin E transcription initiation region (Morrison et al, 2002). Whereas pRB is expected to dissociate from the cyclin E promoter when phosphorylated in late G1, the E2F-Sp1 element was found to remain occupied and to be crucial to transcriptional activation (Botz et al, 1996;Le Cam et al, 1999), suggesting that activating E2Fs remain.…”