Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice

Iglesias, Ainhoa; Murga, Matilde; Laresgoiti, Usua; Skoudy, Anouchka; Bernales, Irantzu; Fullaondo, Asier; Moreno, Bernardino; Lloreta, J.; Field, Seth J.; Real, Francisco X.; Zubiaga, Ana M.

doi:10.1172/jci200418879

Cited by 86 publications

(57 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…E2F1/E2F2 doubleknockout (DKO) pancreatic cells exhibit increased rates of apoptosis as early as postnatal day 15, before manifestations of pancreatic atrophy. 19 To characterize the apoptotic cell death, we isolated pancreatic cells from 2-week-old DKO and wild-type mice and measured changes in mitochondrial membrane potential by examining fluorescence of cells incubated with JC-1 ( Figure 1a). In live cells, JC-1 monomers form aggregates and emit both green and red fluorescence, while in dying cells with collapsed Δψ m , JC-1 is only monomeric and emits exclusively green fluorescence.…”

Section: Resultsmentioning

confidence: 99%

“…Colonies of E2F1 − / − , E2F2 − / − and DKO E2F1 − / − /E2F2 − / − mice have been described. 19,51,52 p53 − / − and p21 CIP1 − / − mice have also been described. 25,53 DKO E2F1 − / − /E2F2 − / − mice were bred to p53 − / − or p21 CIP1 − / − mice to generate TKO E2F1 − / − /E2F2 − / − /p53 − / − or E2F1 − / − /E2F2 − / − /p21 CIP1 − / − animals.…”

Section: Methodsunclassified

“…DKO pancreas is overtly normal until the second week of postnatal age, 19 suggesting that E2F1 and E2F2 are dispensable for the timely cellular proliferation occurring up to this age in pancreas. During terminal differentiation, in contrast, they appear to have a major role as repressors of the cell cycle by promoting attenuation of DNA replication.…”

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 99%

“…We and others have previously reported that combined inactivation of E2F1 and E2F2 transcription factors leads to exocrine and endocrine pancreatic dysfunction, causing diabetes and the collapse of the entire pancreas. 18,19 After a period of strong cell division cycles, which take place during embryonic development and finalize by the second week after birth, pancreatic tissue is virtually post-mitotic. 20 By contrast, pancreatic cells lacking E2F1 and E2F2 continue cycling aberrantly well beyond this age.…”

mentioning

confidence: 99%

“…20 By contrast, pancreatic cells lacking E2F1 and E2F2 continue cycling aberrantly well beyond this age. 19 Strikingly, E2F1/E2F2 mutant pancreas exhibits an increased apoptotic rate and the organ degenerates rapidly. 19 Other organs in E2F1/E2F2 DKO mice also show a singular involution, particularly the hematopoietic system, salivary glands and testicles, 19 although the mediators involved in E2F1/E2F2-dependent tissue atrophy have not yet been identified.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsunclassified

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2015

View full text Add to dashboard Cite

show abstract

Cycling through metabolism

Aguilar

Fajas

2010

EMBO Mol Med

View full text Add to dashboard Cite

Since the discovery of cyclins, the role of cell cycle regulators in the control of cell proliferation has been extensively studied. It is clear that proliferation requires an adapted metabolic response of the cells; hence the regulation of cell cycle must be linked to metabolic control. While at a much slower pace, the impact that the activities of cell cycle regulators such as cyclins, cyclin dependent kinases or E2F factor, transcription factor have on cell metabolism are also being uncovered. Here we will focus on recent data implicating cell cycle regulators in metabolic control, with particular attention to studies performed using mouse models. Furthermore, we will discuss the possible relevance of these findings in the context of metabolic disorders such as obesity or diabetes.

show abstract

Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis

Cheung

Hui

Wong

et al. 2022

Intl Journal of Cancer

View full text Add to dashboard Cite

The use of cell cycle inhibitors has necessitated a better understanding of the cell cycle in tumor biology to optimize the therapeutic approach. Cell cycle aberrations are common in cancers, and it is increasingly acknowledged that these aberrations exert oncogenic effects beyond the cell cycle. Multiple facets such as cancer metabolism, immunity and metastasis are also affected, all of which are beyond the effect of cell proliferation alone. This review comprehensively summarized the important recent findings and advances in these interrelated processes. In cancer metabolism, cell cycle regulators can modulate various pathways in aerobic glycolysis, glucose uptake and gluconeogenesis, mainly through transcriptional regulation and kinase activities. Amino acid metabolism is also regulated through cell cycle progression. On cancer metastasis, metabolic plasticity, immune evasion, tumor microenvironment adaptation and metastatic site colonization are intricately related to the cell cycle, with distinct regulatory mechanisms at each step of invasion and dissemination. Throughout the synthesis of current understanding, knowledge gaps and limitations in the literature are also highlighted, as are new therapeutic approaches such as combinational therapy and challenges in tackling emerging targeted therapy resistance. A greater understanding of how the cell cycle modulates diverse aspects of cancer biology can hopefully shed light on identifying new molecular targets by harnessing the vast potential of the cell cycle.

show abstract

Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice

Abstract: Nonstandard abbreviations used: E2F1/E2F2 double-deficient (DKO); expressed sequence tag (EST); microkatal (μkat); murine embryonic fibroblast (MEF).

Cited by 86 publications

References 41 publications

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

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

Cycling through metabolism

Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis

Contact Info

Product

Resources

About