PMID- 23686339
OWN - NLM
STAT- MEDLINE
DCOM- 20130627
LR  - 20211203
IS  - 1095-9203 (Electronic)
IS  - 0036-8075 (Print)
IS  - 0036-8075 (Linking)
VI  - 340
IP  - 6138
DP  - 2013 Jun 14
TI  - Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of 
      progeria.
PG  - 1330-3
LID - 10.1126/science.1238880 [doi]
AB  - Several progeroid disorders, including Hutchinson-Gilford progeria syndrome 
      (HGPS) and restrictive dermopathy (ZMPSTE24 deficiency), arise when a 
      farnesylated and methylated form of prelamin A accumulates at the nuclear 
      envelope. Here, we found that a hypomorphic allele of isoprenylcysteine carboxyl 
      methyltransferase (ICMT) increased body weight, normalized grip strength, and 
      prevented bone fractures and death in Zmpste24-deficient mice. The reduced ICMT 
      activity caused prelamin A mislocalization within the nucleus and triggered 
      prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) 
      signaling, which abolished the premature senescence of Zmpste24-deficient 
      fibroblasts. ICMT inhibition increased AKT-mTOR signaling and proliferation and 
      delayed senescence in human HGPS fibroblasts but did not reduce the levels of 
      misshapen nuclei in mouse and human cells. Thus, targeting ICMT might be useful 
      for treating prelamin A-associated progeroid disorders.
FAU - Ibrahim, Mohamed X
AU  - Ibrahim MX
AD  - Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, 
      Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, S-41390 
      Gothenburg, Sweden.
FAU - Sayin, Volkan I
AU  - Sayin VI
FAU - Akula, Murali K
AU  - Akula MK
FAU - Liu, Meng
AU  - Liu M
FAU - Fong, Loren G
AU  - Fong LG
FAU - Young, Stephen G
AU  - Young SG
FAU - Bergo, Martin O
AU  - Bergo MO
LA  - eng
GR  - P01 HL090553/HL/NHLBI NIH HHS/United States
GR  - R01 AG035626/AG/NIA NIH HHS/United States
GR  - R01 HL086683/HL/NHLBI NIH HHS/United States
GR  - R01 HL089781/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130516
PL  - United States
TA  - Science
JT  - Science (New York, N.Y.)
JID - 0404511
RN  - 0 (Lamin Type A)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Protein Precursors)
RN  - 0 (prelamin A)
RN  - EC 2.1.1.- (Protein Methyltransferases)
RN  - EC 2.1.1.100 (protein-S-isoprenylcysteine O-methyltransferase)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.- (Zmpste24 protein, mouse)
SB  - IM
CIN - Science. 2013 Jun 14;340(6138):1299-300. PMID: 23766322
MH  - Animals
MH  - Cell Nucleus/metabolism
MH  - Cellular Senescence/genetics
MH  - Disease Models, Animal
MH  - Fibroblasts/metabolism
MH  - *Gene Knockout Techniques
MH  - Hand Strength
MH  - Humans
MH  - Lamin Type A
MH  - Membrane Proteins/genetics/*metabolism
MH  - Metalloendopeptidases/genetics/*metabolism
MH  - Methylation
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Nuclear Proteins/metabolism
MH  - Progeria/physiopathology/*therapy
MH  - Protein Methyltransferases/*genetics/*metabolism
MH  - Protein Precursors/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Weight Gain/genetics
PMC - PMC4295631
MID - NIHMS652465
EDAT- 2013/05/21 06:00
MHDA- 2013/06/29 06:00
PMCR- 2015/01/15
CRDT- 2013/05/21 06:00
PHST- 2013/05/21 06:00 [entrez]
PHST- 2013/05/21 06:00 [pubmed]
PHST- 2013/06/29 06:00 [medline]
PHST- 2015/01/15 00:00 [pmc-release]
AID - science.1238880 [pii]
AID - 10.1126/science.1238880 [doi]
PST - ppublish
SO  - Science. 2013 Jun 14;340(6138):1330-3. doi: 10.1126/science.1238880. Epub 2013 
      May 16.