E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

Abstract

Tissue homeostasis requires tight regulation of cellular proliferation, differentiation and apoptosis. E2F1 and E2F2 transcription factors share a critical role in tissue homeostasis, since their combined inactivation results in overall organ involution, specially affecting the pancreatic gland, which subsequently triggers diabetes. We have examined the mechanism by which these E2Fs regulate tissue homeostasis. We show that pancreas atrophy in E2F1/E2F2 double-knockout (DKO) mice is associated with mitochondrial apoptosis and activation of the p53 pathway in young animals, before the development of diabetes. A deregulated expression of E2F target genes was detected in pancreatic cells of young DKO animals, along with unscheduled DNA replication and activation of a DNA damage response. Importantly, suppression of DNA replication in vivo with aphidicolin led to a significant inhibition of the p53 pathway in DKO pancreas, implying a causal link between DNA replication stress and p53 activation in this model. We further show that activation of the p53 pathway has a key role in the aberrant phenotype of DKO mice, since targeted inactivation of p53 gene abrogated cellular apoptosis and prevented organ involution and insulin-dependent diabetes in mice lacking E2F1/E2F2. Unexpectedly, p53 inactivation unmasked oncogenic features of E2F1/E2F2-depleted cells, as evidenced by an accelerated tumor development in triple-knockout mice compared with p53 − / − mice. Collectively, our data reveal a role for E2F1 and E2F2 as suppressors of replicative stress in differentiating cells, and uncover the existence of a robust E2F-p53 regulatory axis to enable tissue homeostasis and prevent tumorigenesis. These findings have implications in the design of approaches targeting E2F for cancer therapy.

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

“…Abnormal DNA replication in E2F1/2 knockout cells can activate the p53 pathway and then generate p53-dependent apoptosis to prevent the occurrence of tumor, but when p53 is also inactivated, it promotes tumor development. The powerful E2F-p53 regulatory axis has the function of maintaining tissue homeostasis and preventing tumorigenesis [ 30 ]. Another reports suggested that the targeted inactivation of E2F1–3 leads to cell cycle stagnation at G1 / S and G2 / M, and when p53 and p21 are also inactivated, cells resume cell cycle progression and continue to grow.…”

MicroRNA-125a Regulates Cell Proliferation Via Directly Targeting E2F2 in Osteosarcoma

“…It mainly binds to the retinoblastoma protein, Prb, in a cell cycle-dependent manner to regulate downstream cell cycle and expression of proliferation-associated proteins [28]. In addition, E2F1 and E2F2 maintain the steady state of cells together with p53 protein, and an imbalance in these proteins leads to tumorigenesis [29]. Besides, E2F2 can promote cell transformation by regulating G1 to S phase transition [30].…”

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

“…Abnormal DNA replication in E2F1/2 knockout cells will activate the p53 pathway and then generate p53-dependent apoptosis to prevent the occurrence of tumor, but when p53 is also inactivated, it promotes tumor development. The powerful E2F-p53 regulatory axis has the function of maintaining tissue homeostasis and preventing tumorigenesis [30]. Another reports suggested that the targeted inactivation of E2F1-3 leads to cell cycle stagnation at G1 / S and G2 / M, and when p53 and p21 are also inactivated, cells resume cell cycle progression and continue to grow.…”