A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells

© 2021, Chen et al..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:10

Enthalten in:

eLife - 10(2021) vom: 02. Feb.

Sprache:

Englisch

Beteiligte Personen:

Chen, Xue [VerfasserIn]
Yao, Haidong [VerfasserIn]
Kashif, Muhammad [VerfasserIn]
Revêchon, Gwladys [VerfasserIn]
Eriksson, Maria [VerfasserIn]
Hu, Jianjiang [VerfasserIn]
Wang, Ting [VerfasserIn]
Liu, Yiran [VerfasserIn]
Tüksammel, Elin [VerfasserIn]
Strömblad, Staffan [VerfasserIn]
Ahearn, Ian M [VerfasserIn]
Philips, Mark R [VerfasserIn]
Wiel, Clotilde [VerfasserIn]
Ibrahim, Mohamed X [VerfasserIn]
Bergo, Martin O [VerfasserIn]

Links:

Volltext

Themen:

Cell biology
EC 2.1.1.-
EC 2.1.1.100
HGPS
ICMT
Inhibitor
Journal Article
Lamin Type A
Methylation
Mouse
Prelamin A
Progeria
Protein Methyltransferases
Protein-S-isoprenylcysteine O-methyltransferase
Pyrans
Research Support, Non-U.S. Gov't
Senescence

Anmerkungen:

Date Completed 02.02.2022

Date Revised 02.02.2022

published: Electronic

Citation Status MEDLINE

doi:

10.7554/eLife.63284

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM320871975