Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts

Sagan, Daniel; Mörtl, Simone; Müller, Irene; Eckardt‐Schupp, Friederike; Eichholtz-Wirth, H

doi:10.1007/s10495-006-0021-0

Cited by 14 publications

(16 citation statements)

References 54 publications

(69 reference statements)

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“…This antibody has been shown to be effective in several cell lines to induce receptor clustering and apoptosis (Fanzo et al, 2003;Sagan et al, 2007).…”

Section: Ch11 Treatment Of Erythrocytesmentioning

confidence: 99%

CD95 is not functional in human erythrocytes

Sagan

Jermnim

Tangvarasittichai

2010

Int J Lab Hematology

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“…This antibody has been shown to be effective in several cell lines to induce receptor clustering and apoptosis (Fanzo et al, 2003;Sagan et al, 2007).…”

Section: Ch11 Treatment Of Erythrocytesmentioning

confidence: 99%

CD95 is not functional in human erythrocytes

Sagan

Jermnim

Tangvarasittichai

2010

Int J Lab Hematology

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“…They have previously been successfully used in several studies dealing with the enhanced radiosensitivity of patients with genetic disorders like Nijmegen breakage syndrome or ataxia teleangiectasia [20,28]. In our hands, LCLs proved to be ineffective for detecting differences in radiationinduced cell death in patients without defined genetic alterations.…”

Section: Discussionmentioning

confidence: 97%

Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity

Greve

Dreffke

Rickinger³

et al. 2009

Apoptosis

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In the present study, the predictive value of ionising radiation (IR)-induced cell death was tested in peripheral blood lymphocytes (PBLs) and their corresponding Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) in an interlaboratory comparison. PBLs and their corresponding LCLs were derived from 15 tumour patients, that were considered clinically radiosensitive based on acute side-effects, and matched controls. Upon coding of the samples, radiosensitivity of the matched pairs was analysed in parallel in three different laboratories by assessing radiation-induced apoptotic and necrotic cell death using annexin V. All participating laboratories detected a dose-dependent increase of apoptosis and necrosis in the individual samples, to a very similar extent. However, comparing the mean values of apoptotic and necrotic levels derived from PBLs of the radiosensitive cohort with the mean values of the control cohort did not reveal a significant difference. Furthermore, within 15 matched pairs, no sample was unambiguously and independently identified by all three participating laboratories to demonstrate in vitro hypersensitivity that matched the clinical hypersensitivity. As has been reported previously, apoptotic and necrotic cell death is barely detectable in immortalised LCL derivatives using low doses of IR. Concomitantly, the differences in apoptosis or necrosis levels found in primary cells of different individuals were not observed in the corresponding LCL derivatives. All participating laboratories concordantly reasoned that, with the methods applied here, IR-induced cell death in PBLs is unsuitable to unequivocally predict the individual clinical radiosensitivity of cancer patients. Furthermore, LCLs do not reflect the physiological properties of the corresponding primary blood lymphocytes with regard to IR-induced cell death. Their value to predict clinical radiosensitivity is thus highly questionable.

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“…Clearly nibrin is required for radiation induced apoptosis and the p70-nibrin product of the hypomorphic c.657 661del5 mutation is sufficient to uphold this function. Indeed, even enhanced apoptosis has been previously reported in irradiated NBS patient cells [33] and in a haploinsufficient mouse model [34]. Furthermore, the early embryonic lethality of Nbn null mutants was due to massive apoptosis [8].…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo

Wessendorf¹,

Vijg²,

Nussenzweig³

et al. 2014

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Nibrin (NBN) is a member of a DNA repair complex together with MRE11 and RAD50. The complex is associated particularly with the repair of DNA double strand breaks and with the regulation of cell cycle check points. Hypomorphic mutation of components of the complex leads to human disorders characterised by radiosensitivity and increased tumour occurrence, particularly of the lymphatic system. We have examined here the relationship between DNA damage, mutation frequency and mutation spectrum in vitro and in vivo in mouse models carrying NBN mutations and a lacZ reporter plasmid. We find that NBN mutation leads to increased spontaneous DNA damage in fibroblasts in vitro and high basal mutation rates in lymphatic tissue of mice in vivo. The characteristic mutation spectrum is dominated by single base transitions rather than the deletions and complex rearrangements expected after abortive repair of DNA double strand breaks. We conclude that in the absence of wild type nibrin, the repair of spontaneous errors, presumably arising during DNA replication, makes a major contribution to the basal mutation rate. This applies also to cells heterozygous for an NBN null mutation. Mutation frequencies after irradiation in vivo were not increased in mice with nibrin mutations as might have been expected considering the radiosensitivity of NBS patient cells in vitro. Evidently apoptosis is efficient, even in the absence of wild type nibrin.

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Enhanced CD95-mediated apoptosis contributes to radiation hypersensitivity of NBS lymphoblasts

Cited by 14 publications

References 54 publications

CD95 is not functional in human erythrocytes

CD95 is not functional in human erythrocytes

Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity

Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo

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