Life and death decisions by E2F-1

Bell, L. Andrew; Ryan, Kevin M.

doi:10.1038/sj.cdd.4401324

Cited by 141 publications

(140 citation statements)

References 86 publications

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“…E2F1 is a transcription factor involved in cell-cycle control and apoptosis, whose expression is often dysregulated in human tumors. 32,33 Upon DNA damage, E2F1 is phosphorylated by CHK1 and CHK2 and subsequently induces transcription of p73 and its target genes to initiate p53-independent apoptosis. 34 Studies on murine embryonic fibroblasts indicated that the AHR inhibits E2F1-induced apoptosis, probably due to a physical interaction of both transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27 KIP1 and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer. With an annual incidence of two to three million new cases worldwide, non-melanoma skin cancer (NMSC) is one of the most frequent forms of cancer in humans (World Health Organization; http://www.who.int/uv/faq/skincancer/en/index1 .html). Typically, NMSCs, such as basal cell and squamous cell carcinomas, occur on sun-exposed areas of the skin, indicating that solar ultraviolet (UV) radiation, especially its UVB part (290-320 nm), is the most important etiological factor. 1,2 In fact, it is well established that UVB radiation gives rise to skin cancer without additional initiators or promoters and thus is a complete carcinogen. 1 Because of the thinning of the ozone layer, the increase in recreational sunbathing and the enhanced usage of UV tanning beds, the incidence of NMSC is expected to increase in future years, 1,2 underscoring the urgent need for novel preventives against UV-induced skin malignancies.When skin is exposed to solar radiation, high-energy UVB photons penetrate into the epidermis and initiate the so-called UVB response. 3 The main trigger of this stress response is the absorbance of UVB rays by DNA, which leads to the generation of highly mutagenic DNA photoproducts. 3,4 In addition, UVB exposure results in the formation...

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Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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“…The transcriptional activator E2F1 has been shown to upregulate the expression of many genes involved in differentiation, proliferation and apoptosis, and it plays a major role in the G1/S transition and DNA synthesis (Bell and Ryan, 2004). Prohibitin represses the transcriptional activity of E2Fs1-5 by recruiting co-repressors, including histone deacetylase 1, N-CoR and BrG1/ Brm (Wang et al, 2002), whereas Rb represses the transcriptional activity of E2Fs1-3 by recruiting histone deacetylase 1, DNA methyltransferase and BrG1/Brm (Luo et al, 1998;Magnaghi-Jaulin et al, 1998;Zhu, 2005).…”

Section: Introductionmentioning

confidence: 99%

Prohibitin interacts with RNF2 and regulates E2F1 function via dual pathways

Choi

Hong

et al. 2007

Oncogene

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Prohibitin, a tumor suppresser protein, plays an important role in the transcriptional regulation of various genes involved in cell-cycle control and proliferation. Recent studies have reported that the growth-suppressive property of the prohibitin protein is exhibited in its physical interaction with E2F family proteins and its subsequent repression of their transcriptional activity. Herein, we report that prohibitin interacts with RING finger protein 2 (RNF2), a member of the PcG (polycomb-group) family of proteins, and that the two proteins regulate the activity of E2F1 via dual pathways: the direct, prohibitin-mediated pathway and the indirect, p16-mediated pathway of E2F1 transcriptional regulation. Co-immunoprecipitation experiments showed that endogenous prohibitin interacts with endogenous RNF2. Interestingly, the expressed amounts of RNF2 and prohibitin were interdependently affected at the post-translational level. Furthermore, the depletion of either endogenous RNF2 or prohibitin using the RNA interference technique increased the level of p16 protein expression, resulting in a decrease in the transcriptional activity of E2F1 via the p16-CDK4-Rb pathway. In addition, chromatin immunoprecipitation assays showed that RNF2 was recruited to E2F1-response promoters along with prohibitin to inhibit the transcriptional activity of E2F1. Cell proliferation was also regulated by the prohibitin-RNF2 interaction. These results suggest that the RNF2-prohibitin complex regulates the activity of E2F1 via dual pathways.

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“…The E2F family of transcription factors is a group of DNA-binding proteins that are involved in cell-cycle progression, and therefore play a key role in cell proliferation (4). E2F1has a more pivotal role than other E2Fs, due to its unique character of inducing both cell-cycle progression and apoptosis (5).…”

Section: Introductionmentioning

confidence: 99%

TGF-β induces growth suppression in multiple myeloma MM.1S cells via E2F1

Liu¹,

Guo²,

Wei³

et al. 2017

Oncology Letters

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Abstract. Transforming growth factor-β (TGF-β) has an important role in multiple target genes and signaling pathways. The E2F family of transcription factors is a group of DNA-binding proteins that are involved in cell-cycle progression, and therefore have a key role in proliferation. The present study demonstrates that inhibition of cell growth by TGF-β occurs in the multiple myeloma cell line MM.1S. However, the growth-suppressive effects of TGF-β may be reversed by small interfering (si)RNA to reduce the expression of E2F1. TGF-β1 and E2F1 siRNA were manipulated in MM.1S cells to investigate the association between these genes. FACScan Flow Cytometer, western blot analysis and other methods were adopted to confirm such interrelation. The present data showed that TGF-β mediated growth suppression in MM.1S cells, while inducing E2F1 protein expression levels rapidly and transiently. The present data support the hypothesis that E2F1 is a central mediator of TGF-β-induced growth suppression in MM.1S cells and control of E2F1 may be a downstream event of TGF-β action, at least in one multiple myeloma cell line.

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Life and death decisions by E2F-1

Cited by 141 publications

References 86 publications

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

Prohibitin interacts with RNF2 and regulates E2F1 function via dual pathways

TGF-β induces growth suppression in multiple myeloma MM.1S cells via E2F1

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