Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent
<p>Abstract</p> <p>Background</p> <p>Deletion or mutation(s) of the survival motor neuron 1 <it>(SMN1) </it>gene causes spinal muscular atrophy (SMA). The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it re...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2009-05-01
|
| Series: | BMC Cell Biology |
| Online Access: | http://www.biomedcentral.com/1471-2121/10/40 |
| _version_ | 1818146818754609152 |
|---|---|
| author | Funanage Vicky L Gómez-Curet Ilsa Wu Chia-Yen Scavina Mena Wang Wenlan |
| author_facet | Funanage Vicky L Gómez-Curet Ilsa Wu Chia-Yen Scavina Mena Wang Wenlan |
| author_sort | Funanage Vicky L |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Deletion or mutation(s) of the survival motor neuron 1 <it>(SMN1) </it>gene causes spinal muscular atrophy (SMA). The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts.</p> <p>Results</p> <p>Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, β-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that β-lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts.</p> <p>Conclusion</p> <p>Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism.</p> |
| first_indexed | 2024-12-11T12:25:24Z |
| format | Article |
| id | doaj.art-5c26f33e739948788b239dff0578dcab |
| institution | Directory Open Access Journal |
| issn | 1471-2121 |
| language | English |
| last_indexed | 2024-12-11T12:25:24Z |
| publishDate | 2009-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cell Biology |
| spelling | doaj.art-5c26f33e739948788b239dff0578dcab2022-12-22T01:07:25ZengBMCBMC Cell Biology1471-21212009-05-011014010.1186/1471-2121-10-40Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independentFunanage Vicky LGómez-Curet IlsaWu Chia-YenScavina MenaWang Wenlan<p>Abstract</p> <p>Background</p> <p>Deletion or mutation(s) of the survival motor neuron 1 <it>(SMN1) </it>gene causes spinal muscular atrophy (SMA). The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts.</p> <p>Results</p> <p>Camptothecin treatment reduced the DNA relaxation activity of DNA topoisomerase I in human fibroblasts. In contrast, kinase activity of DNA topoisomerase I was not affected by camptothecin, because levels of phosphorylated SR proteins were not decreased. Upon camptothecin treatment, levels of p53 were markedly increased. To determine if p53 plays a role in the increased sensitivity of SMA fibroblasts to camptothecin, we analyzed the sensitivity of SMA fibroblasts to another DNA topoisomerase I inhibitor, β-lapachone. This compound is known to induce death via a p53-independent pathway in several cancer cell lines. We found that β-lapachone did not induce p53 activation in human fibroblasts. In addition, SMA and control fibroblasts showed essentially identical sensitivity to this compound. By immunofluorescence staining, SMN and p53 co-localized in gems within the nucleus, and this co-localization was overall reduced in SMA fibroblasts. However, depletion of p53 by siRNA did not lessen the camptothecin sensitivity in SMA fibroblasts.</p> <p>Conclusion</p> <p>Even though p53 and SMN are associated, the increased sensitivity of SMA fibroblasts to camptothecin does not occur through a p53-dependent mechanism.</p>http://www.biomedcentral.com/1471-2121/10/40 |
| spellingShingle | Funanage Vicky L Gómez-Curet Ilsa Wu Chia-Yen Scavina Mena Wang Wenlan Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent BMC Cell Biology |
| title | Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent |
| title_full | Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent |
| title_fullStr | Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent |
| title_full_unstemmed | Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent |
| title_short | Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53-independent |
| title_sort | increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin is p53 independent |
| url | http://www.biomedcentral.com/1471-2121/10/40 |
| work_keys_str_mv | AT funanagevickyl increasedsusceptibilityofspinalmuscularatrophyfibroblaststocamptothecinisp53independent AT gomezcuretilsa increasedsusceptibilityofspinalmuscularatrophyfibroblaststocamptothecinisp53independent AT wuchiayen increasedsusceptibilityofspinalmuscularatrophyfibroblaststocamptothecinisp53independent AT scavinamena increasedsusceptibilityofspinalmuscularatrophyfibroblaststocamptothecinisp53independent AT wangwenlan increasedsusceptibilityofspinalmuscularatrophyfibroblaststocamptothecinisp53independent |