The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome
<p>Abstract</p> <p>Fibroblasts derived from the progeroid Werner syndrome (WS) show reduced replicative lifespan and a “stressed” morphology, both phenotypes being alleviated by using the p38 MAP kinase inhibitor SB203580. Because p38 is a major hub for the control of stress-signal...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2013-01-01
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| Series: | Chemistry Central Journal |
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| Online Access: | http://journal.chemistrycentral.com/content/7/1/18 |
| _version_ | 1818765035564957696 |
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| author | Davis Terence Rokicki Michal J Bagley Mark C Kipling David |
| author_facet | Davis Terence Rokicki Michal J Bagley Mark C Kipling David |
| author_sort | Davis Terence |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Fibroblasts derived from the progeroid Werner syndrome (WS) show reduced replicative lifespan and a “stressed” morphology, both phenotypes being alleviated by using the p38 MAP kinase inhibitor SB203580. Because p38 is a major hub for the control of stress-signalling pathways we were interested in examining the possible role for downstream kinases in order to refine our understanding of the role of p38 signalling in regulation of WS cell growth. To this end we treated WS and normal fibroblasts with MK2 inhibitors to determine whether MK2 inhibition would affect either the growth or morphology of WS cells. The first inhibitor, 7,8-dihydroxy-2,4-diamino-3-cyanobenzopyranopyridine (inhibitor <b>2</b>), resulted in inhibition of WS cell growth and had no effect on morphology, effects that occurred below the level needed to inhibit MK2 and thus suggestive of inhibitor toxicity. The second inhibitor, 2-(2-quinolin-3-ylpyridin-4-yl)-1,5,6,7-tetrahydro-4<it>H</it>-pyrrolo-[3,2-<it>c</it>]pyridin-4-one (<b>CMPD16</b>), resulted in a significant extension of WS fibroblast replicative capacity compared to normal cells. In addition, <b>CMPD16</b> reverted the WS cellular morphology to that seen in normal dermal fibroblasts. These data suggest that MK2 activity plays a substantial role in proliferation control in WS cells. <b>CMPD16</b> was not as effective in cellular lifespan extension as SB203580, however, suggesting that, although MK2 is a downstream kinase involved in cell cycle arrest, other p38 targets may play a role. Alternatively, as <b>CMPD16</b> is toxic to cell growth at levels just above those that extend lifespan, it is possible that the therapeutic window is too small. However, as <b>CMPD16</b> does show significant effects in WS fibroblasts, this acts as proof-of-principle for the efforts to design and synthesise improved MK2 inhibitors. As MK2 is involved in inflammatory processes and inflammation plays a major role in WS phenotypes, these data suggest MK2 as a potential therapeutic target for the treatment of Werner syndrome.</p> |
| first_indexed | 2024-12-18T08:11:41Z |
| format | Article |
| id | doaj.art-a37748b05bac45568e2edce271f3bce1 |
| institution | Directory Open Access Journal |
| issn | 1752-153X |
| language | English |
| last_indexed | 2024-12-18T08:11:41Z |
| publishDate | 2013-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Chemistry Central Journal |
| spelling | doaj.art-a37748b05bac45568e2edce271f3bce12022-12-21T21:14:52ZengBMCChemistry Central Journal1752-153X2013-01-01711810.1186/1752-153X-7-18The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndromeDavis TerenceRokicki Michal JBagley Mark CKipling David<p>Abstract</p> <p>Fibroblasts derived from the progeroid Werner syndrome (WS) show reduced replicative lifespan and a “stressed” morphology, both phenotypes being alleviated by using the p38 MAP kinase inhibitor SB203580. Because p38 is a major hub for the control of stress-signalling pathways we were interested in examining the possible role for downstream kinases in order to refine our understanding of the role of p38 signalling in regulation of WS cell growth. To this end we treated WS and normal fibroblasts with MK2 inhibitors to determine whether MK2 inhibition would affect either the growth or morphology of WS cells. The first inhibitor, 7,8-dihydroxy-2,4-diamino-3-cyanobenzopyranopyridine (inhibitor <b>2</b>), resulted in inhibition of WS cell growth and had no effect on morphology, effects that occurred below the level needed to inhibit MK2 and thus suggestive of inhibitor toxicity. The second inhibitor, 2-(2-quinolin-3-ylpyridin-4-yl)-1,5,6,7-tetrahydro-4<it>H</it>-pyrrolo-[3,2-<it>c</it>]pyridin-4-one (<b>CMPD16</b>), resulted in a significant extension of WS fibroblast replicative capacity compared to normal cells. In addition, <b>CMPD16</b> reverted the WS cellular morphology to that seen in normal dermal fibroblasts. These data suggest that MK2 activity plays a substantial role in proliferation control in WS cells. <b>CMPD16</b> was not as effective in cellular lifespan extension as SB203580, however, suggesting that, although MK2 is a downstream kinase involved in cell cycle arrest, other p38 targets may play a role. Alternatively, as <b>CMPD16</b> is toxic to cell growth at levels just above those that extend lifespan, it is possible that the therapeutic window is too small. However, as <b>CMPD16</b> does show significant effects in WS fibroblasts, this acts as proof-of-principle for the efforts to design and synthesise improved MK2 inhibitors. As MK2 is involved in inflammatory processes and inflammation plays a major role in WS phenotypes, these data suggest MK2 as a potential therapeutic target for the treatment of Werner syndrome.</p>http://journal.chemistrycentral.com/content/7/1/18Werner syndromeSenescencep38MAP kinaseMK2MAPKAPK2StressAgeingSignalling |
| spellingShingle | Davis Terence Rokicki Michal J Bagley Mark C Kipling David The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome Chemistry Central Journal Werner syndrome Senescence p38 MAP kinase MK2 MAPKAPK2 Stress Ageing Signalling |
| title | The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome |
| title_full | The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome |
| title_fullStr | The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome |
| title_full_unstemmed | The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome |
| title_short | The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome |
| title_sort | effect of small molecule inhibition of mapkapk2 on cell ageing phenotypes of fibroblasts from human werner syndrome |
| topic | Werner syndrome Senescence p38 MAP kinase MK2 MAPKAPK2 Stress Ageing Signalling |
| url | http://journal.chemistrycentral.com/content/7/1/18 |
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