TY - JOUR
T1 - Impaired regulation of 3-hydroxy-3-methylglutaryl-coenzyme a reductase degradation in lovastatin-resistant cells
AU - Ravid, Tommer
AU - Avner, Rachel
AU - Polak-Charcon, Sylvie
AU - Faust, Jerry R.
AU - Roitelman, Joseph
PY - 1999/10/8
Y1 - 1999/10/8
N2 - L-90 cells were selected to grow in the presence of serum lipoproteins and 90 μM lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (IMGR). L-90 cells massively accumulate IMGR, a result of > 10-fold amplification of the gene and 40-fold rise in mRNA, and also overexpress other enzymes of the mevalonate pathway. Western blot and promoter-luciferase analyses indicate that transcriptional regulation of sterol-responsive genes by 25-hydroxycholesterol or mevalonate is normal. Yet, none of these genes is regulated by lipoproteins, a result of severe impairment in the low density lipoprotein receptor pathway. Moreover, L-90 cells do not accelerate the degradation of HMGR or transfected HMGal chimera in response to 25- hydroxycholesterol or mevalonate. This aberrant phenotype persists when cells are grown without lovastatin for up to 37 days. The inability to regulate HMGR degradation is not due to its overproduction since in LP-90 cells, which were selected for lovastatin resistance in lipoprotein-deficient serum, HMGR is overexpressed, yet its turnover is regulated normally. Also, the rapid degradation of transfected α subunit of T cell receptor is markedly retarded in L-90 cells. These results show that in addition to gene amplification and overexpression of cholesterogenic enzymes, statin resistance can follow loss of regulated HMGR degradation.
AB - L-90 cells were selected to grow in the presence of serum lipoproteins and 90 μM lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (IMGR). L-90 cells massively accumulate IMGR, a result of > 10-fold amplification of the gene and 40-fold rise in mRNA, and also overexpress other enzymes of the mevalonate pathway. Western blot and promoter-luciferase analyses indicate that transcriptional regulation of sterol-responsive genes by 25-hydroxycholesterol or mevalonate is normal. Yet, none of these genes is regulated by lipoproteins, a result of severe impairment in the low density lipoprotein receptor pathway. Moreover, L-90 cells do not accelerate the degradation of HMGR or transfected HMGal chimera in response to 25- hydroxycholesterol or mevalonate. This aberrant phenotype persists when cells are grown without lovastatin for up to 37 days. The inability to regulate HMGR degradation is not due to its overproduction since in LP-90 cells, which were selected for lovastatin resistance in lipoprotein-deficient serum, HMGR is overexpressed, yet its turnover is regulated normally. Also, the rapid degradation of transfected α subunit of T cell receptor is markedly retarded in L-90 cells. These results show that in addition to gene amplification and overexpression of cholesterogenic enzymes, statin resistance can follow loss of regulated HMGR degradation.
UR - http://www.scopus.com/inward/record.url?scp=0032832568&partnerID=8YFLogxK
U2 - 10.1074/jbc.274.41.29341
DO - 10.1074/jbc.274.41.29341
M3 - Article
C2 - 10506194
AN - SCOPUS:0032832568
SN - 0021-9258
VL - 274
SP - 29341
EP - 29351
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -