Mutation of E2F2 in Mice Causes Enhanced T Lymphocyte Proliferation, Leading to the Development of Autoimmunity

Murga, Matilde; Fernández‐Capetillo, Oskar; Field, Seth J.; Moreno, Bernardino; Borlado, Luis R.; Fujiwara, Yuko; Balomenos, Dimitrios; Vicario, A.; Carrera, Ana C.; Orkin, Stuart H.; Greenberg, Michael E.; Zubiaga, Ana M.

doi:10.1016/s1074-7613(01)00254-0

Cited by 152 publications

(172 citation statements)

References 44 publications

(2 reference statements)

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“…These results argue for a positive role for E2F1-3 in cell cycle progression. By contrast, we and others have shown that loss of E2F2, or more dramatically, the combined loss of E2F1 and E2F2 impairs cellular quiescence and leads to accelerated replication of DNA of several cell types, implying a negative role for these proteins in proliferation control (Murga et al, 2001;Zhu et al, 2001;Infante et al, 2008;Pusapati et al, 2010). Moreover, loss of E2F leads to deficient erythropoiesis, which has been associated with increased DNA double-stranded breaks and cell cycle arrest (Dirlam et al, 2007), although the source of the DNA damage has not been identified.…”

Section: Introductioncontrasting

confidence: 66%

“…In line with the original model of E2F function, overexpression of E2F1 in immortalized quiescent rodent fibroblasts results in increased DNA replication and cell proliferation (Lukas et al, 1996), and overexpression of E2F2 in thymic epithelial cells results in the development of thymomas (Scheijen et al, 2004). Furthermore, knockout of E2F1 in mouse embryo fibroblasts or in T lymphocytes modestly slows progression from quiescence to S phase (Wang et al, 1998;Murga et al, 2001), and E2F2 À/À and E2F1/E2F2 À/À mice exhibit impaired hematopoiesis resulting from defective S-phase progression in progenitor populations (Li et al, 2003). The combined inactivation of E2F1, 2 and 3 completely abolishes entry into S phase and proliferation, along with reduced expression of E2F target genes necessary for these processes (Wu et al, 2001).…”

Section: Introductionmentioning

confidence: 57%

“…Colonies of E2F1 À/À , E2F2 À/À and double knockout E2F1/ E2F2 À/À mice have been described (Field et al, 1996;Murga et al, 2001;Iglesias et al, 2004). p21 CIP1À/À mice (Balomenos et al, 2000) were a kind gift from Dimitrios Balomenos.…”

Section: Mouse Strainsmentioning

confidence: 99%

“…Instead, they are critical for restraining cellular division in monocyte progenitors during their concomitant differentiation into macrophages. A similar mechanism may be operating in proliferating T cells and keratinocytes lacking E2F2 or E2F1/E2F2 (Murga et al, 2001;Infante et al, 2008;Pusapati et al, 2010). The role of E2F1/E2F2, and possibly also E2F3, as activators could be limited to ES or early progenitor cells, in which the levels of phosphorylated Rb may be sufficiently high to prevent transcriptional repressor complex recruitment to E2F targets.…”

mentioning

confidence: 99%

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Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence

et al. 2010

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E2F1-3 proteins appear to have distinct roles in progenitor cells and in differentiating cells undergoing cell cycle exit. However, the function of these proteins in paradigms of terminal differentiation that involve continued cell division has not been examined. Using compound E2F1/E2F2-deficient mice, we have examined the effects of E2F1 and E2F2 loss on the differentiation and simultaneous proliferation of bone-marrow-derived cells toward the macrophage lineage. We show that E2F1/ E2F2 deficiency results in accelerated DNA replication and cellular division during the initial cell division cycles of bone-marrow-derived cells, arguing that E2F1/E2F2 are required to restrain proliferation of pro-monocyte progenitors during their differentiation into macrophages, without promoting their cell cycle exit. Accelerated proliferation is accompanied by early expression of DNA replication and cell cycle regulators. Remarkably, rapid proliferation of E2F1/E2F2 compound mutant cultures is temporally followed by induction of a DNA damage response and the implementation of a p21 CIP1 -dependent senescence. We further show that differentiating E2F1/E2F2-knockout macrophages do not trigger a DNA damage response pathway in the absence of DNA replication. These findings underscore the relevance of E2F1 and E2F2 as suppressors of hematopoietic progenitor expansion. Our data indicate that their absence in differentiating macrophages initiates a senescence program that results from enforcement of a DNA damage response triggered by DNA hyper-replication.

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Section: Introductioncontrasting

confidence: 66%

Section: Introductionmentioning

confidence: 57%

Section: Mouse Strainsmentioning

confidence: 99%

mentioning

confidence: 99%

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Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence

et al. 2010

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“…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

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

et al. 2015

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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.

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Diverse roles for CDK‐associated activity during spermatogenesis

2019

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The primary function of cyclin‐dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical cell cycle‐associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly, several CDKs exhibit meiosis‐specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis‐specific functions are mediated by both known CDK/cyclin complexes and meiosis‐specific CDK‐regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins, suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.

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Mutation of E2F2 in Mice Causes Enhanced T Lymphocyte Proliferation, Leading to the Development of Autoimmunity

Cited by 152 publications

References 44 publications

Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence

Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence

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

Diverse roles for CDK‐associated activity during spermatogenesis

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