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Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy-
3-methylglutaryl coenzyme A reductase gene expression in normal and
leukemic cells
S Vitols, S Norgren, G Juliusson, L Tatidis and H Luthman
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm,
Sweden.
Altered cholesterol homeostasis has been noted in malignant cells, which
led us to explore the regulation of cholesterol metabolism in normal and
leukemic cells. The mean low-density lipoprotein (LDL) receptor and
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities were
fivefold and threefold higher in mononuclear blood cells from 33 patients
with leukemia, compared with cells from 23 healthy subjects, whereas
elevations in RNA levels were twofold and 40% only. The activities of the
two proteins correlated in normal cells (r = .46), whereas an inverse
correlation was found in leukemic cells (r = -.40). Relatively weak
correlations were found between LDL receptor RNA levels and receptor
activity in normal (r = .48) and leukemic cells (r = .49), and HMG-CoA
reductase RNA levels correlated (r = .53) with reductase activity in
leukemic cells only. The ratios of protein activities to RNA levels in
cells were constant during consecutive blood samplings and similar in
leukemic blood and bone marrow cells from the same individual. During
cholesterol deprivation, protein activities increased more than RNA levels,
and leukemic cells with high LDL receptor activity showed a partial
resistance to the suppressing effect of sterols on LDL receptor gene
expression. The results demonstrate that LDL receptor RNA levels alone can
not explain variation in receptor activity, suggesting post-RNA regulation
of LDL receptor expression, similar to what has been described for HMG-CoA
reductase. Taken together, the present results suggest multilevel
regulation of both proteins and demonstrate that each cell clone, normal or
malignant, has a unique ratio of protein activity to RNA level. Leukemic
cells, in contrast to normal cells, can meet increased cholesterol
requirements by either elevated LDL receptor activity or increased
cholesterol synthesis, which is of potential interest for diagnosis and
specific treatment of leukemia.
Volume 84,
Issue 8,
pp. 2689-2698,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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