Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

Berton, Thomas R.; Mitchell, David L.; Guo, Ruifeng; Johnson, D. Gale

doi:10.1038/sj.onc.1208462

Cited by 56 publications

(70 citation statements)

References 79 publications

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“…Moreover, we show that both E2F1 and E2F3 are able to bind the DDB2 promoter. The recent finding from Berton et al (2005) showing that E2F1-deficient mice have impaired DNA repair supports our finding that E2F affects DNA repair by means of regulation of repair proteins including DDB2. Intriguingly both DDB2 and E2F1-3 are normally cell cycle regulated.…”

Section: Ddb2 Is Expressed In Mouse Tissues and Affects Dna Repairsupporting

confidence: 90%

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells

Prost

Caldwell

et al. 2006

Oncogene

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DDB2, a gene mutated in XPE patients, is involved in global genomic repair especially the repair of cyclobutane pyrimidine dimers (CPDs), and is regulated by p53 in human cells. We show that DDB2 is expressed in mouse tissues and demonstrate, using primary mouse epithelial cells, that mouse DDB2 is regulated by E2F transcription factors. Retinoblastoma (Rb), a tumor suppressor critical for the control of cell cycle progression, regulates E2F activity. Using Cre-Lox technology to delete Rb in primary mouse hepatocytes, we show that DDB2 gene expression increases, leading to elevated DDB2 protein levels. Furthermore, we show that endogenous E2F1 and E2F3 bind to DDB2 promoter and that treatment with E2F1-antisense or E2F1-small interfering RNA (siRNA) decreases DDB2 transcription, demonstrating that E2F1 is a transcriptional regulator for DDB2. This has consequences for global genomic repair: in Rb-null cells, where E2F activity is elevated, global DNA repair is increased and removal of CPDs is more efficient than in wild-type cells. Treatment with DDB2-siRNA decreases DDB2 expression and abolishes the repair phenotype of Rb-null cells. In summary, these results identify a new regulatory pathway for DDB2 by E2F, which does not require but is potentiated by p53, and demonstrate that DDB2 is involved in global repair in mouse epithelial cells.

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Section: Ddb2 Is Expressed In Mouse Tissues and Affects Dna Repairsupporting

confidence: 90%

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells

Prost

Caldwell

et al. 2006

Oncogene

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“…However, we and others discovered that, for UV radiation, inactivating E2f1 restores wild-type levels of UVB-induced apoptosis to p53 Ϫ/Ϫ cells (3,4). This result implicates an underlying direct apoptosis pathway that is separately activated by UVB and is p53-independent in the sense of being active in a p53 knockout cell (provided E2f1 is also absent).…”

mentioning

confidence: 70%

Bcl-2 is the target of a UV-inducible apoptosis switch and a node for UV signaling

Knezevic

Zhang

Rochette

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Sunlight's UVB radiation triggers cell signaling at multiple sites to induce apoptosis. The integration of these signal entry sites is not understood. Here we show that P53 and E2f1 constitute a UVinducible apoptosis switch. At low-UV doses, wild-type cells resemble the OFF state of an siP53-treated cell, whereas at high-UV doses, the apoptosis frequency transitions to the fully ON behavior of an siE2f1-treated cell. The switch's target is Bcl-2: Rapid Bcl-2 down-regulation in response to UVB-induced DNA photoproducts is lost in P53-deficient cells, but, as for apoptosis, is restored when both P53 and its inhibited target E2f1 are absent. P53's downregulation of Bcl-2 is mediated entirely through E2f1. Bcl-2 is also down-regulated by a separate pathway triggered by DNA photoproducts in the absence of P53 and E2f1. Four UV pathways terminating on Bcl-2 contribute to apoptosis after UVB irradiation. The apoptosis lost in p53 ؊/؊ is completely restored by siBcl-2, implying that Bcl-2 is a rate-limiting member of this network. These results identify Bcl-2 as an integrator of several UV-induced proapoptotic signals and show that it, in turn, suppresses a direct UVapoptosis pathway. UV-induced apoptosis requires both UV activation of the direct pathway and a separate UV disinhibition of this pathway through P53-E2f1-Bcl-2.E2f1 ͉ P53 ͉ stress response ͉ network ͉ systems biology

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“…Silibinin Up-regulates E2F1 and Decreases E2F2, E2F3, p53, p21, and p27 Proteins and Apoptosis in Skin Chronically Exposed to UVB F2F1 is elevated and stabilized when cells or animals are exposed to DNA-damaging agents, such as UV (9,14,15). No reports show the effects of long-term chronic UVB exposure on E2F1 level in skin, an exposure that mimic those in humans that lead to nonmelanoma skin cancers.…”

Section: Resultsmentioning

confidence: 99%

“…6 -8]. The antiapoptotic activity of E2F1 is an important response to UVB-induced DNA damage because DNA repair is stimulated and apoptosis suppressed (9,10), suggesting that targeting these molecules could be a mechanism-based approach to protect skin against UVB-caused damage and photocarcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Differential effect of silibinin on E2F transcription factors and associated biological events in chronically UVB-exposed skin versus tumors in SKH-1 hairless mice

Gu¹,

Singh²,

Dhanalakshmi³

et al. 2006

Molecular Cancer Therapeutics

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UVB radiation -induced DNA damage in skin activates cellular pathways involved in DNA repair, cell cycle regulation, and apoptosis, important events that prevent conversion of damaged skin cells into cancer. We reported recently the efficacy of silibinin against photocarcinogenesis along with altered molecular events in tumors (Cancer Research, 64:6349 -56, 2004). The molecular and biological events modulated by silibinin in chronically UVB-irradiated skin leading to cancer prevention, however, are not known. Herein, we describe effect of silibinin on skin 15 and 25 weeks after UVB exposure and compared them with molecular alterations in skin tumors. UVB decreased E2F1 but increased E2F2 and E2F3 protein levels in skin, and these were reversed by silibinin treatment. Silibinin-induced E2F1 was accompanied by an inhibition of apoptosis and decreases in p53 and cyclin-dependent kinase inhibitors. Silibinin-caused decrease in E2F2 and E2F3 was accompanied by reduced levels of cyclin-dependent kinases, cyclins, CDC25C, and mitogen-activated protein kinases and Akt signaling and inhibition of cell proliferation. In tumorigenesis protocols, topical or dietary silibinin significantly inhibited tumor appearance and growth. As opposed to UVB-exposed skin, UVB-induced tumors showed elevated levels of E2F1, but these were reduced in silibinin-treated tumors without any effect on E2F2 and E2F3. Contrary to the inhibition of apoptosis and p53 expression in UVBexposed skin cells, silibinin increased these variables in tumors. These differential effects of silibinin on E2F1 versus E2F2 and E2F3 and their associated molecular alterations and biological effects in chronic UVB-exposed skin suggest their role in silibinin interference with photocarcinogenesis.

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Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

Cited by 56 publications

References 79 publications

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells

E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells

Bcl-2 is the target of a UV-inducible apoptosis switch and a node for UV signaling

Differential effect of silibinin on E2F transcription factors and associated biological events in chronically UVB-exposed skin versus tumors in SKH-1 hairless mice

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