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Volume 270,
Number 10,
Issue of March 10, 1995 pp. 5462-5468
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Rapid Decline in
Folylpolyglutamate Synthetase Activity and Gene Expression during
Maturation of HL-60 Cells
NATURE OF THE EFFECT, IMPACT ON FOLATE COMPOUND POLYGLUTAMATE
POOLS, AND EVIDENCE FOR PROGRAMMED DOWN-REGULATION DURING MATURATION
(Received for publication, September 13,
1994; and in revised form, December 22, 1994)
Mary G.
Egan
,
Sonia
Sirlin
,
Brigitta
G.
Rumberger
,
Timothy A.
Garrow
,
Barry
Shane
,
Francis
M.
Sirotnak
These studies in HL-60 cells examined the regulation of
folylpolyglutamate synthetase (FPGS) activity at the level of gene
expression during terminal maturation. Following addition of 210 mM Me SO to cultures of HL-60 cells at a concentration
that induces maturation of 85-90% of the cells, FPGS activity,
but not folylpolyglutamate hydrolase (FPGH) activity, was reduced
2-7-fold within 1-5 days. The initial decline in FPGS
activity preceded any effect of Me SO on rate of growth and
the increase in appearance of nitro blue tetrazoliumpositive cells, a
marker of cellular maturation, and the decrease after 5 days of
exposure to Me SO was solely accounted for by a 7-fold
decrease in value for V . The same time and
concentration dependence for Me SO was shown for the decline
in FPGS activity, increase in nitro blue tetrazolium-positive cells,
and decline in the level of a 2.1-kilobase FPGS mRNA during exposure to
this inducer. This decline in FPGS mRNA was reversible when
Me SO was removed from the culture medium but only until
that time when an appreciable number of cells were committed to
terminal maturation. Following growth of HL-60 cells with
[ H]MTX, used as a model folate compound, a large
reduction in its intracellular polyglutamate pools was shown during
maturation which quantitatively reflected the decline in FPGS activity
as well as folate transport inward (Sirotnak, F. M., Jacobson, D. M.,
and Yang, C-H.(1986) J. Biol. Chem. 261, 11150-11156).
Other data showed that folate status or obviation of the folate
requirement during growth of these cells strongly influenced the
rapidity of the onset of maturation following exposure to inducer.
Overall, these results show that FPGS activity in HL-60 cells is a
marker for proliferative capacity and that the underlying basis for the
decline in FPGS activity during maturation is altered cognate gene
expression which is manifested as early reversible and late
irreversible phases. They also suggest that the coordinate reduction
observed in folate transport, FPGS activity, dihydrofolate reductase,
and probably other folate related enzymes by limiting macromolecular
biosynthesis may be early programmed events in the maturation process
that influence the switch from proliferation to senescence in these
cells.

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Copyright © 1995 by the American Society for Biochemistry and Molecular Biology.
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