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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2721-2729
Induced Differentiation of U937 Cells by 1,25-dihydroxyvitamin
D3 Involves Cell Cycle Arrest in G1 That Is Preceded by
a Transient Proliferative Burst and an Increase in Cyclin
Expression
Nynke Y. Rots,
Antonio Iavarone,
Virginia Bromleigh, and
Leonard
P. Freedman
From the Cell Biology Program, Memorial Sloan-Kettering Cancer
Center, Sloan-Kettering Division, Graduate School of Medical Sciences,
Cornell University, New York, NY.
The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3
[1,25(OH)2D3], is a potent inhibitor of
cellular proliferation as well as an inducer of differentiation of
myeloid leukemic cells to macrophages. We have previously reported that
a number of genes are upregulated by
1,25(OH)2D3 during myeloid differentiation, including the cyclin-dependent kinase (CDK) inhibitors p21, p27, 15, and p18, suggesting that cell cycle arrest and differentiation are
tightly linked processes. We further explore here the relationship between growth inhibition and differentiation. We report that, upon
1,25(OH)2D3 treatment, U937 cells exhibited an
early proliferative burst followed by growth inhibition and subsequent
differentiation. Although CDK levels remain constant throughout, this
transient increase in proliferation was accompanied by increases in
cyclin A, D1, and E protein levels. p21 and p27 levels were also
elevated during both the proliferative burst and subsequent inhibition of cell growth. Ectopic overexpression of p21 and/or p27 in U937 cells,
in the absence of hormone, resulted in an induction of the expression
of monocyte/macrophage-specific markers, whereas overexpression of p15
and p18 had no effect, suggesting that a subset of CDK inhibitors are
important for both growth arrest and differentiation and that an early
increase in proliferation is somehow a prerequisite for subsequent
differentiation. However, no such biphasic behavior was detected in
cells that are growth inhibited by 1,25(OH)2D3
but do not differentiate, such as MCF-7 cells. Taken together, these
results indicate that both growth stimulation and subsequent inhibition
precede differentiation and involve induction of both cyclins and p21
and p27, whereas cell cycle arrest of differentiated cells can be
achieved simply by elevations in CDK inhibitors.
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