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Nijmegen breakage syndrome fibroblasts expressing the C-terminal truncated NBN(p70) protein undergo p38/MK2-dependent premature senescence.

Davis T, Tivey HS, Brook AJ, Kipling D - Biogerontology (2014)

Bottom Line: Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres.A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2.These data suggest that NBN(p70) expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK, davist2@cardiff.ac.uk.

ABSTRACT
Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal fibroblasts. A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2. These data suggest that NBN(p70) expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome.

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Growth characteristics of NBS cells. a example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle), 2.5 µM SB203580 (fill circle), 2.5 µM BIRB 796 (open square) or 0.5 µM VX-745 (fill square). b example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle) or 5.0 µM MK2.III (fill circle): note that the NBSp70 cells had already achieved 5.6 PDs prior to starting the growth experiment. c comparison of the mean replicative capacity for control NBSp70 cells and NBSp70 cells treated with SB203580 or MK2.III (Student’s t-test)
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Fig1: Growth characteristics of NBS cells. a example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle), 2.5 µM SB203580 (fill circle), 2.5 µM BIRB 796 (open square) or 0.5 µM VX-745 (fill square). b example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle) or 5.0 µM MK2.III (fill circle): note that the NBSp70 cells had already achieved 5.6 PDs prior to starting the growth experiment. c comparison of the mean replicative capacity for control NBSp70 cells and NBSp70 cells treated with SB203580 or MK2.III (Student’s t-test)

Mentions: Primary NBSp70 fibroblasts were grown to senescence in DMEM either with no supplementation, or in medium that had been supplemented with various p38 or MK2 inhibitors (illustrated in Fig. 1a, b). Control NBSp70 fibroblasts had a replicative capacity of 19.6 ± 3.0 PDs (Table 1) that was statistically different (p < 0.036) from the mean replicative capacity of eight NDF strains of 38.8 ± 10.5 PDs (Table S1). The NBSp70 replicative capacity was less than that of all the normal fibroblasts strains used.Fig. 1


Nijmegen breakage syndrome fibroblasts expressing the C-terminal truncated NBN(p70) protein undergo p38/MK2-dependent premature senescence.

Davis T, Tivey HS, Brook AJ, Kipling D - Biogerontology (2014)

Growth characteristics of NBS cells. a example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle), 2.5 µM SB203580 (fill circle), 2.5 µM BIRB 796 (open square) or 0.5 µM VX-745 (fill square). b example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle) or 5.0 µM MK2.III (fill circle): note that the NBSp70 cells had already achieved 5.6 PDs prior to starting the growth experiment. c comparison of the mean replicative capacity for control NBSp70 cells and NBSp70 cells treated with SB203580 or MK2.III (Student’s t-test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4305097&req=5

Fig1: Growth characteristics of NBS cells. a example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle), 2.5 µM SB203580 (fill circle), 2.5 µM BIRB 796 (open square) or 0.5 µM VX-745 (fill square). b example growth curves in PDs versus days for primary NBSp70 cells supplemented with 0.1 % (v/v) DMSO (open circle) or 5.0 µM MK2.III (fill circle): note that the NBSp70 cells had already achieved 5.6 PDs prior to starting the growth experiment. c comparison of the mean replicative capacity for control NBSp70 cells and NBSp70 cells treated with SB203580 or MK2.III (Student’s t-test)
Mentions: Primary NBSp70 fibroblasts were grown to senescence in DMEM either with no supplementation, or in medium that had been supplemented with various p38 or MK2 inhibitors (illustrated in Fig. 1a, b). Control NBSp70 fibroblasts had a replicative capacity of 19.6 ± 3.0 PDs (Table 1) that was statistically different (p < 0.036) from the mean replicative capacity of eight NDF strains of 38.8 ± 10.5 PDs (Table S1). The NBSp70 replicative capacity was less than that of all the normal fibroblasts strains used.Fig. 1

Bottom Line: Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres.A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2.These data suggest that NBN(p70) expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK, davist2@cardiff.ac.uk.

ABSTRACT
Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal fibroblasts. A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2. These data suggest that NBN(p70) expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome.

Show MeSH
Related in: MedlinePlus