TY - JOUR
T1 - Assessing the effi cacy of protein farnesyltransferase inhibitors in mouse models of progeria
AU - Yang, Shao H.
AU - Chang, Sandy Y.
AU - Andres, Douglas A.
AU - Spielmann, H. Peter
AU - Young, Stephen G.
AU - Fong, Loren G.
PY - 2010/2/1
Y1 - 2010/2/1
N2 - Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna HG/+). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna nHG/+) develop progeria-like disease phenotypes. The fact that Lmna nHG/+ mice manifest disease raised the possibility that the benefi cial effects of an FTI in Lmna HG/+ mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna HG/+ and Lmna nHG/+ mice. In Lmna HG/+ mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna nHG/+ mice. The failure of the FTI to ameliorate disease in Lmna nHG/+ mice supports the idea that the benefi cial effects of an FTI in Lmna HG/+ mice are due to the effect of drug on the farnesylation of progerin.-Yang, S. H., S. Y. Chang, D. A. Andres, H. P. Spielmann, S. G. Young, and L. G. Fong. Assessing the effi cacy of protein farnesyltransferase inhibitors in mouse models of progeria.
AB - Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna HG/+). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna nHG/+) develop progeria-like disease phenotypes. The fact that Lmna nHG/+ mice manifest disease raised the possibility that the benefi cial effects of an FTI in Lmna HG/+ mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna HG/+ and Lmna nHG/+ mice. In Lmna HG/+ mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna nHG/+ mice. The failure of the FTI to ameliorate disease in Lmna nHG/+ mice supports the idea that the benefi cial effects of an FTI in Lmna HG/+ mice are due to the effect of drug on the farnesylation of progerin.-Yang, S. H., S. Y. Chang, D. A. Andres, H. P. Spielmann, S. G. Young, and L. G. Fong. Assessing the effi cacy of protein farnesyltransferase inhibitors in mouse models of progeria.
KW - Aging
KW - Farnesylation
KW - Knock in mice
KW - Lamin A
KW - Posttranslational modifi cations
KW - Protein farnesyltransferase
KW - Protein prenylation
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U2 - 10.1194/jlr.M002808
DO - 10.1194/jlr.M002808
M3 - Article
C2 - 19965595
AN - SCOPUS:77949527805
SN - 0022-2275
VL - 51
SP - 400
EP - 405
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 2
ER -