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.
Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria