A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells
| العنوان: | A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells |
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| المؤلفون: | Jianjiang Hu, Maria Eriksson, Clotilde Wiel, Ian M. Ahearn, Ting Wang, Staffan Strömblad, Martin O. Bergo, Elin Tüksammel, Muhammad Kashif, Mohamed X. Ibrahim, Mark R. Philips, Haidong Yao, Gwladys Revêchon, Yiran Liu, Xue Chen |
| المصدر: | eLife eLife, Vol 10 (2021) |
| بيانات النشر: | eLife Sciences Publications, Ltd, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, senescence, Vascular smooth muscle, Mouse, Cell, Mice, 0302 clinical medicine, Biology (General), Aorta, Cellular Senescence, Mice, Knockout, Progeria, integumentary system, General Neuroscience, General Medicine, Methylation, Lamin Type A, Progerin, Phenotype, Cell biology, inhibitor, medicine.anatomical_structure, Medicine, HGPS, ICMT, Senescence, congenital, hereditary, and neonatal diseases and abnormalities, QH301-705.5, Science, Myocytes, Smooth Muscle, Short Report, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, medicine, Animals, Humans, Protein Methyltransferases, Gene, Cell Proliferation, Pyrans, General Immunology and Microbiology, progeria, nutritional and metabolic diseases, Cell Biology, medicine.disease, Disease Models, Animal, 030104 developmental biology, methylation, 030217 neurology & neurosurgery |
| الوصف: | A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS. |
| تدمد: | 2050-084X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4025cace094c6dcae00415bb8b599c8c https://doi.org/10.7554/elife.63284 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4025cace094c6dcae00415bb8b599c8c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
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