A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells
| Autor: | 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 |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | eLife eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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