Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition

Christmann, Markus; Tomičić, Maja; Origer, Judith; Kaina, Bernd

doi:10.1038/sj.onc.1208994

Cited by 34 publications

(32 citation statements)

References 34 publications

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“…Our mass spectrometric analysis following immunoprecipitation by anti-KIAA0101 antibody identified POLD1 and FEN1 to be interacting partners with KIAA0101, as well as PCNA, and it is presumed that KIAA0101 is very likely to be a member of a DNA-replication complex with POLD1, FEN1, and PCNA in replication foci. Furthermore, we here showed that KIAA0101 expression was regulated by the p53-p21 pathway, like PCNA, POLD1, and FEN1 (17)(18)(19). KIAA0101 interaction with PCNA could be inhibited by p21 competitively (5), and both expression and function of KIAA0101 could be strictly regulated by the p53-p21 pathway as one of the critical factors of DNA replication.…”

Section: Discussionmentioning

confidence: 83%

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Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer

et al. 2007

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To isolate novel diagnostic markers and therapeutic targets for pancreatic cancer, we earlier did expression profile analysis of pancreatic cancer cells using a genome-wide cDNA microarray combined with microdissection. Among dozens of trans-activated genes in pancreatic cancer cells, this study focused on KIAA0101 whose overexpression in pancreatic cancer cells was validated by immunohistochemical analysis. KIAA0101 was previously identified as p15 PAF [proliferating cell nuclear antigen (PCNA)-associated factor] to bind with PCNA; however, its function remains unknown.

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Section: Discussionmentioning

confidence: 83%

“…The expressions of several DNA replication factors, such as PCNA (17), POLD1 (18), and FEN1 (19), were regulated by p53 pathway. Our extensive expression analysis for p53-regulated genes using cDNA microarray (20) also found a possibility that KIAA0101 expression was down-regulated by adenovirus-mediated introduction of p53 (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer

et al. 2007

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“…However, in some cell types, including mouse embryonic fibroblasts (MEFs), p53 preferentially acts in an antiapoptotic manner (Lackinger and Kaina, 2000;Christmann et al, 2005;Tomicic et al, 2005a). This is explained by a predominant role of p53 in DNA repair (Christmann et al, 2003).…”

mentioning

confidence: 99%

Topotecan Triggers Apoptosis in p53-Deficient Cells by Forcing Degradation of XIAP and Survivin Thereby Activating Caspase-3-Mediated Bid Cleavage

Tomičić

Christmann²,

Kaina³

2009

J Pharmacol Exp Ther

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The topoisomerase I inhibitor topotecan (TPT) is used in the therapy of different tumors including high-grade gliomas. We previously showed that TPT-induced apoptosis depends on p53 with p53 wild-type (wt) cells being more resistant because of p53-controlled degradation of topoisomerase I. Here, we show that p53-deficient (p53 Ϫ/Ϫ ) fibroblasts undergo excessive mitochondrial apoptosis featuring H2AX phosphorylation, Bcl-x L decline, cytochrome c release, caspase-9/-3/-2 activation, and cleavage of Bid. In wt and apaf-1 Ϫ/Ϫ cells, caspase-2 did not become activated and Bid was not cleaved. In addition, p53Ϫ/Ϫ cells cotreated with TPT and caspase-3 inhibitor showed neither caspase-2 activation nor Bid cleavage, implying that caspase-2 is processed downstream of the apoptosome by caspase-3. Although processing of caspase-9/-3 was similar in wt and p53 Ϫ/Ϫ cells, only p53 Ϫ/Ϫ cells displayed active caspase-3. This was due to the proteasomal degradation of X-chromosome-linked inhibitor of apoptosis (XIAP) and survivin that inhibits caspase-3 activity. Accordingly, TPT-induced apoptosis in wt cells was increased after XIAP/survivin knockdown. Silencing of Bid led to reduction of TPT-triggered apoptosis. Data obtained with mouse fibroblasts could be extended to human glioma cells. In U87MG (p53wt) cells cotreated with TPT and pifithrin-␣, or transfected with p53-siRNA, caspase-2 and Bid were significantly cleaved and XIAP/survivin was degraded. Furthermore, the knockdown of XIAP and survivin led to increased TPT-triggered apoptosis. Overall, the data show that p53-deficient/depleted cells are hypersensitive to TPT because they down-regulate XIAP and survivin, and thus amplify the intrinsic apoptotic pathway via caspase-3-mediated Bid cleavage. Therefore, in gliomas harboring wild-type p53, TPT-based therapy might be improved by targeted down-regulation of XIAP and survivin.Topotecan (TPT) is a camptothecin derivative that belongs to the class of topoisomerase I (topoI) inhibitors. It is used in the therapy of different types of cancer including pediatric high-grade gliomas. After the formation of a DNA single-strand break, topoI remains covalently bound to the 3Ј end of the DNA phosphodiester backbone forming the topoI-DNA-cleavable complex (Nitiss and Wang, 1996), which is a reversible intermediate catalyzing the cleavagereligation reaction of the enzyme (Porter and Champoux, 1989). TopoI inhibitors such as TPT stabilize this complex preventing the religation of topoI-mediated single-strand breaks (Hertzberg et al., 1989). The cytotoxicity of topoI inhibitors is limited to the S phase of the cell cycle and is triggered by a collision of the replication fork with the inhibitor-stabilized cleavable complex. This results in blockage of fork movement and finally the formation of toxic DNA double-strand breaks (DSBs) (Hsiang et al., 1989;Goldwasser et al., 1996). These DSBs induce a checkpoint response by activation of upstream kinases like ataxia telangiectasia-mutated (ATM), ataxia telangiectasia and Rad3-relate...

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“…Although FEN1 is generally regarded as a tumor suppressor gene, many studies have reported that it is highly expressed in proliferative cancer cells and is essential for cell growth and proliferation in tumor tissues (9)(10)(11). Notably, FEN1 expression is significantly upregulated by chemotherapy (5) and other genotoxic stresses, such as DNA-alkylating drugs (12) and radiation treatment (13). Conversely, downregulation of FEN1 enhances cancer cell sensitivity to chemotherapies such as temozolomide, platinum, mitomycin C, and taxol (5,14), which suggests that FEN1 expression is associated with the efficacy of anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells

Zeng

Che

Liu

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.

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Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition

Cited by 34 publications

References 34 publications

Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer

Oncogenic Role of KIAA0101 Interacting with Proliferating Cell Nuclear Antigen in Pancreatic Cancer

Topotecan Triggers Apoptosis in p53-Deficient Cells by Forcing Degradation of XIAP and Survivin Thereby Activating Caspase-3-Mediated Bid Cleavage

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells

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