Expression and DNA binding activity of the Ku heterodimer in bladder carcinoma

Stronati, Laura; Gensabella, G.; Lamberti, C.; Barattini, Paola; Frasca, Daniela; Tanzarella, Caterina; Giacobini, S.; Toscano, Maria Gabriella; Santacroce, Costantino; Danesi, Donatella Tirindelli

doi:10.1002/1097-0142(20011101)92:9<2484::aid-cncr1598>3.0.co;2-7

Cited by 23 publications

(14 citation statements)

References 37 publications

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“…In tumour-transformed tissue in both squamous cell carcinoma and adenocarcinoma, on the other hand, positive immunostaining was found for all three proteins but to a variable extent. This is in agreement with other studies, in which DNAPKcs, Ku86 and Ku70 were found to be upregulated in tumour tissue from bladder and colorectal carcinoma, as compared with the corresponding non-tumour tissue (Stronati et al, 2001;Hosoi et al, 2004). It has also been shown that DNA damage response proteins, such as ATM, Chk2, p53 and g-H2AX are constitutively activated and expressed at higher levels during early tumorigenesis as compared to normal tissue (Bartkova et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB–IIA of cervical cancer

et al. 2006

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The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB -IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P ¼ 0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT.

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Section: Discussionsupporting

confidence: 93%

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB–IIA of cervical cancer

et al. 2006

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“…They also observed a decrease in phosphorylated Ku expression in the cytoplasm and a parallel increase in the nucleus after exposure to radiation. 24) Our results and these findings suggest that, when DSBs are generated by radiation, DNA-PKcs and Ku70 might increase and up-regulate the DNA-PK activity in OSCC. The up-regulation of DNA-PK activity plays a key role in DSBs repair after radiation therapy.…”

Section: Discussionsupporting

confidence: 54%

Up‐regulation of DNA‐dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma

et al. 2003

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DNA-PK is a nuclear protein with serine/threonine kinase activity and forms a complex consisting of the DNA-PKcs and a heterodimer of Ku70 and Ku80 proteins. Recent laboratory experiments have demonstrated that the DNA-PK complex formation is one of the major pathways by which mammalian cells respond to DNA double-strand breaks induced by ionizing radiation. In this study, we evaluated the relationship between expression levels of DNA-PKcs, Ku70 and Ku80 proteins and radiation sensitivity in oral squamous cell carcinoma (OSCC) cell lines and in OSCC patients treated with preoperative radiation therapy. The OSCC cell lines greatly differed in their response to irradiation, as assessed by a standard colony formation assay. However, the expression levels of the DNA-PK complex proteins were all similar, and there was no association between the magnitude of their expression and the tumor radiation sensitivity. Expression of DNA-PK complex proteins increased after radiation treatment, and the in- he DNA-PK complex is one of the major pathways by which cells respond to DNA double-strand breaks (DSBs). The DNA-PK complex consists of a heterodimer comprising 70-and 80-kDa proteins termed Ku and a 465-kDa serine/ threonine protein kinase catalytic subunit termed DNA-PKcs. 1)The Ku (p70/p80) component functions as an activator of the catalytic subunit, and also represents the major double-stranded DNA binding protein.1, 2) DNA-PK plays an important role in the repair of DSBs and in V(D)J recombination.3) Tumor cell lines defective in the expression of either Ku or DNA-PKcs exhibit marked radiation sensitivity. Cells lacking DNA-PK activity because of defects in DNA-PK components, such as human malignant glioma M059J cells and cells derived from scid mice, show hypersensitivity to ionizing radiation.3-7) These previous laboratory findings suggested that DNA-PK is a candidate as a predictor of cellular radiation sensitivity. There is, however, little information on the expression of DNA-PK in primary human tumors and the correlation, if any, with radiation sensitivity, though the results are not definitive. [8][9][10][11] Therefore, the aim of this study is to evaluate the relationship between expression levels of DNA-PK complex proteins and radiation sensitivity. Materials and MethodsCell culture. All SCC cell lines were grown in Ham/F12: DMEM (1:1) supplemented with 10% fetal bovine serum, 24 µg/ml adenine, 0.4 µg/ml hydrocortisone and 50 units/ml penicillin and streptomycin. The HSC2, HSC3 and HSC 4 cell lines were provided by Japanese Collection Research Bioresources. The SCC15, SCC25, SCC66 and SCC111 cell lines were provided by Dr.

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“…Studies of ATM and Ku80 expression in tumor tissues have yielded inconsistent findings across different cancer types, with some reporting higher expression, some reporting lower expression, and others reporting no changes. 12,19,20,[25][26][27] The inconsistency in ATM and Ku80 regulation in different tumor types suggests a remarkable difference on the molecular alterations related to the progression of cancer at different sites. In addition, the methodology of measuring mRNA expression and the selection of control genes also may contribute to the inconsistency of results.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 Recent reports 10,18 suggest that a positive relation exists between Ku and cancer development. Higher levels of Ku or DNA-PKcs expression have been identified in bladder, 19 colon, 20 nasopharyngeal, 21 and cervical 22 tumor tissues compared with corresponding normal tissues. The expression patterns of Ku and DNA-PKcs also reportedly have been associated with tumor radiosensitivity and survival in patients with rectal, 23 nasopharynx, 21 and cervical 22 carcinomas.…”

mentioning

confidence: 99%

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Xing

Vaporciyan

et al. 2008

Cancer

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BACKGROUND.The double‐strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia‐telangiectasia mutated (ATM), DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs), and the Ku heterodimeric regulatory complex 86‐kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.METHODS.mRNA expression levels of ATM, DNA‐PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real‐time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan‐Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.RESULTS.mRNA expression of ATM and DNA‐PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA‐PKcs were associated significantly with a 1.82‐fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13‐fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan‐Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA‐PKcs had notably shorter median survival than patients with low ratios.CONCLUSIONS.The current findings suggested that the T/N expression ratios of ATM and DNA‐PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy. Cancer 2008. ©2008 American Cancer Society.

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Expression and DNA binding activity of the Ku heterodimer in bladder carcinoma

Cited by 23 publications

References 37 publications

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB–IIA of cervical cancer

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB–IIA of cervical cancer

Up‐regulation of DNA‐dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

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