The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage

Zio, Daniela De; Bordi, Matteo; Tino, E; Lanzuolo, Chiara; Ferraro, Elisabetta; Mora, Eugenio Meza; Ciccosanti, Fabiola; Fimia, Gian María; Orlando, Valerio; Cecconi, Francesco

doi:10.1038/cdd.2010.125

Cited by 23 publications

(24 citation statements)

References 42 publications

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“…Apoptotic protease activating factor 1 (APAF1) is a crucial component of the apoptosome that is present in humans and mice (24,25) and is assembled in response to cellular stress, including DNA damage, hypoxia and oncogene activation (26–28). APAF1 is closely related to several oncogenes and tumor suppressor genes, including B-cell lymphoma-2 (Bcl-2) and p53 (29,30).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer

Huang

et al. 2017

International Journal of Oncology

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MicroRNAs are a class of small non-coding, endogenous RNAs involved in cancer development and progression. MicroRNA-221 (mir-221) has been reported to have both an oncogenic and tumor-suppressive role in human tumors, but the role of miR-221 in ovarian cancer is poorly understood. In the present study, the expression levels of miR-221 and the apoptosis protease activating factor 1 (APAF1) protein in 63 samples of ovarian cancer tissues and the cell lines, IOSE25, A2780, OVCAR3, SKOV3 and 3AO were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell proliferation was measured using Cell Counting kit-8 (CCK-8); cell migration and invasion were detected using a Transwell assay; cell apoptosis was evaluated by flow cytometry and Hoechst staining, and a luciferase assay was performed to verify a putative target site of miR-221 in the 3′-UTR of APAF1 mRNA. Expression of miR-221 was upregulated in ovarian cancer tissues. Patients with increased miR-221 expression levels had a reduced disease-free survival (P=0.0014) and overall survival (P=0.0058) compared with those with low miR-221 expression. Transfection of SKOV3 and A2780 cell lines with miR-221 inhibitor induced APAF1 protein expression, suppressed cell proliferation and migration and promoted tumor cell apoptosis. In conclusion, the APAF1 gene was confirmed as a direct target of miR-221 and overexpression of APAF1 suppressed ovarian cancer cell proliferation and induced cell apoptosis in vitro. These findings indicate that miR-221-APAF1 should be studied further as a potential new diagnostic or prognostic biomarker for ovarian cancer.

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Section: Introductionmentioning

confidence: 99%

Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer

Huang

et al. 2017

International Journal of Oncology

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“…3). It has been shown that Ku can regulate the expression of Apaf1, a pro-apoptotic protein which is fundamental for the execution of the mitochondrial apoptotic pathway (26). Ku-mediated Apaf1 regulation is dynamically modulated on DNA damage: As soon as DNA is damaged, Ku protects cells from apoptosis by blocking Apaf1 transcription; when the DNA damage accumulates highly inside the cells, Ku leaves the Apaf1 promoter, thereby contributing both to the up-regulation of its expression and to the occurrence of apoptosis.…”

Section: Kumentioning

confidence: 99%

New Insights into the Link Between DNA Damage and Apoptosis

Zio

Cianfanelli

Cecconi

2013

Antioxidants & Redox Signaling

101

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Significance: When lesions are unrepaired or there are defects in the DNA repair system, DNA damage is often correlated to apoptosis. However, different kinds of lesions and different degrees of lesion severity can trigger numerous signaling responses. Recent Advances: DNA repair proteins involved in specific DNA repair pathways can modulate the function or activity of some apoptotic factors, further emphasizing the crosstalk between DNA damage and cell death. Critical Issues: Here, we discuss the signaling networks that link DNA damage to apoptosis, and we focus on post-translational modifications, leading to crucial changes in protein behavior, following various kinds of DNA damage. Moreover, we analyze the existence of apoptosis-related functions of typical repair proteins, leading to diverse, often-overlapping, DNA damage responses. Future Directions: The better understanding of the regulation and the functionality of key DNA repair proteins, also involved in apoptosis regulation, has the potential of modulating the cell outcomes on DNA damage, particularly in the context of cancer treatment. Antioxid. Redox Signal. 19, 559-571.

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“…Both epigenetic and transcriptional factor-mediated regulation of Apaf-1 and PC-9 expression levels plays an important role in predisposition of cells to activate the apoptosome apparatus (4)(5)(6)(7)(8). However, the processes of apoptosome assembly and functioning in cancer cells are under a variety of negative and positive modes of post-translational regulation (9,10).…”

Section: Introductionmentioning

confidence: 99%

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

et al. 2012

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Abstract. The Apaf-1 interacting protein (APIP) and the uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) belong to endogenous regulators of the apoptosome apparatus, but their role in tumourigenesis and progression of non-small cell lung carcinoma (NSCLC) is not known. Previous studies demonstrated that APIP inhibits the apoptosome-mediated procaspase-9 activation while UACA induces translocation of Apaf-1 from the cytoplasm into the nucleus. Here, we report for the first time that the expression of APIP and UACA genes is down-regulated on the level of both mRNA and protein in NSCLC cells and tumours. In particular, the expression of APIP protein was strikingly decreased and the expression of UACA mRNA and protein was frequently down-regulated in NSCLC tumours of different histopathological types. Moreover, stage IA NSCLC tumours showed significantly lower expression of UACA mRNA compared to higher stage tumours. The weak increase of both APIP and UACA mRNA levels in the 5-aza-2'-deoxycytidine-treated NSCLC cells indicates that mechanisms other than DNA methylation are involved in the regulation of APIP and UACA gene expression in these cancer cells. Taken together, the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP-mediated suppression and UACA-assisted Apaf-1 nuclear entry. Moreover, the loss of UACA-assisted Apaf-1 nuclear translocation may underlie the failure of DNA damage checkpoint activation in NSCLC cells leading to their genomic instability. IntroductionThe apoptosome apparatus is a stress-induced cell death signalling platform that is assembled in the cytosol via the cytochrome-c (cyt-c)-and (d)ATP-mediated formation of an Apaf-1 heptameric complex, which recruits and activates the apoptosis initiator procaspase-9 (PC-9) (1-3). Both epigenetic and transcriptional factor-mediated regulation of Apaf-1 and PC-9 expression levels plays an important role in predisposition of cells to activate the apoptosome apparatus (4-8). However, the processes of apoptosome assembly and functioning in cancer cells are under a variety of negative and positive modes of post-translational regulation (9,10). There is evidence that the hypersensitivity of certain malignant neoplasms such as brain tumours and breast carcinomas, as opposed to their normal tissue counterparts, to the cyt-c-induced apoptosis is due to up-regulation of Apaf-1 and its regulator PHAPI, respectively, in cancer cells (11,12). On the other hand, deficient signalling in the apoptosome pathway, due to the lack of apoptosome core component expression or apoptosome dysfunction, contributes to tumourigenesis and progression of malignant neoplasms as well as to their chemo-and radioresistance (8,(13)(14)(15)(16)(17)(18)(19)(20).The activation of apoptosome apparatus is often impaired in non-small cell lung carcinoma (NSCLC) cells and tissues (21,22). The molecular basis of apoptosome apparatus suppression in NSCLC is sti...

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The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage

Cited by 23 publications

References 42 publications

Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer

Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer

New Insights into the Link Between DNA Damage and Apoptosis

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

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