EB病毒之潛伏膜蛋白1透過PI3K/Akt/FOXO3a路徑抑制人類表皮細胞的DNA修復能力

陳逸人

doi:10.6342/NTU.2008.01685

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EB病毒之潛伏膜蛋白1透過PI3K/Akt/FOXO3a路徑抑制人類表皮細胞的DNA修復能力

Epstein-Barr Virus Latent Membrane Protein 1 Represses DNA Repair through the PI3K/Akt/FOXO3a Pathway in Human Epithelial Cells

陳逸人 , Ph.D　　Advisor：陳振陽　　

繁體中文 DOI： 10.6342/NTU.2008.01685

EB病毒；潛伏膜蛋白1 ； PI3K/Akt訊號傳遞路徑； FOXO3a轉錄因子； DNA修復蛋白質DDB1 ；基因體不穩定性； EBV ； LMP1 ； PI3K/Akt signaling pathway ； FOXO3a ； DDB1 ； DNA repair ； Genomic instability

Abstract │ Reference (306) │ Altmetrics

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Latent membrane protein 1 (LMP1), an Epstein-Barr virus (EBV) oncoprotein, mimics a constitutively activated tumor necrosis factor receptor and activates various signaling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt. LMP1 is essential for EBV-mediated B-cell transformation and is sufficient to transform several cell lines. Cellular transformation has been associated strongly with genomic instability, while DNA repair plays an important role in maintaining genomic stability. Previously, we have shown that LMP1 represses DNA repair by the C-terminal activating region 1 (CTAR1) in human epithelial cells. In the present study, we demonstrate that the PI3K/Akt pathway is required for LMP1-mediated repression of DNA repair. Through the LMP1/PI3K/Akt pathway, FOXO3a, which can induce DNA repair, is inactivated because of phosphorylation and relocalization. Expression of a constitutively active FOXO3a mutant can rescue LMP1-mediated repression of DNA repair. Furthermore, LMP1 can decrease the expression of DNA damage-binding protein 1 (DDB1), which functions in nucleotide excision repair, through the PI3K/Akt/FOXO3a pathway. LMP1-mediated repression of DNA repair is restored by DDB1, although only partially. These results suggest that LMP1 triggers the PI3K/Akt pathway to inactivate FOXO3a and decrease DDB1, which can lead to repression of DNA repair and may contribute to genomic instability in human epithelial cells.

Reference ( 306 ) 〈TOP〉

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Adimoolam S, Ford JM. 2002. p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci U S A 99(20):12985-12990.
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連結：
Atkinson PG, Coope HJ, Rowe M, Ley SC. 2003. Latent membrane protein 1 of Epstein-Barr virus stimulates processing of NF-kappa B2 p100 to p52. J Biol Chem 278(51):51134-51142.
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