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Cell Biology & Molecular Biology Programs, Memorial Sloan-Kettering Cancer Center and Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, NY 10021
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ABSTRACT |
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 TOP ABSTRACT FUNCTIONAL AND STRUCTURAL...CLONING AND CHARACTERIZATION OF...REFERENCES |
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KEY WORDS: • vitamin D receptor • dimerization • myeloid cell differentiation • target genes
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FUNCTIONAL AND STRUCTURAL ASPECTS OF VDR ACTION |
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TOPABSTRACTFUNCTIONAL AND STRUCTURAL...CLONING AND CHARACTERIZATION OF...REFERENCES |
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Several studiesindicate that ligand binding induces a conformational change in
receptor structure, and several putative transcriptional cofactors
associate with nuclear receptors in a ligand-dependent fashion.
Structural studies in fact indicate that major conformation changes
occur within the nuclear receptor ligand-binding domain
(LBD)3that permit interactions with coactivators at specific sites within the
LBD. Several groups have also reported that ligands have a profound
influence on nuclear receptor dimerization. This also appears to be the
case for the vitamin D-3 receptor (VDR). We showed that
1,25(OH)2D3 destabilizes a DNA-bound VDR
homodimer, and at the same time favors the formation of a retinoid-X
receptor (RXR)-VDR heterodimer (Cheskis and Freedman 1994
). The ligand for RXR, 9-cis retinoic acid (RA),
in turn destabilizes the RXR-VDR heterodimer and induces RXR
homodimerization. Further, we have used a sensitive kinetic assay,
surface plasmon resonance (SPR), to expand on these findings and have
found that receptor interactions also take place off DNA in solution
(Cheskis and Freedman 1996
). These results, summarized
in model form in Figure 1
,may have important implications in explaining the role of ligands in
nuclear receptor action in vivo, in that target gene selectivity can be
highly influenced by ligands, i.e., RXR-VDR heterodimers will activate
some genes, and RXR homodimers will activate others, and the ligands
clearly affect the equilibrium between the dimer species.
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). Overexpression of RXR enhances
1,25(OH)2D3 induction in the presence of VDR,
and 9-cis RA and other RXR-specific ligands attenuate this
effect. Conversely, when VDR is overexpressed,
1,25(OH)2D3 attenuates 9-cis RA
induction from an RXR-responsive element (RXRE). These effects,
however, appear to be very sensitive to both the relative ratios of the
two receptors as well as their respective target elements; at high RXR
levels, 9-cis RA attenuation is lost, and the ligand can
actually confer costimulation with 1,25(OH)2D3.
When VDR and RXR were overexpressed with both VDR response element
(VDRE) and RXR-response element (RXRE) reporters, the enhancement of
transcription from the VDRE by 1,25(OH)2D3 was
actually reduced relative to that with VDR overexpressed alone, the
opposite of what is observed with the VDRE reporter alone. In effect,
the RXRE may be sequestering RXR.
Although VDR can bind as a homodimer to the osteopontin gene
(OPN) VDRE (Freedman et al. 1994
), our in vivo results
strongly argue against a role for VDR homodimers as transactivators
because 9-cis RA would not be expected to affect VDR if RXR
were not part of the dimer complex, and the net effect of
1,25(OH)2D3 in vitro is to drive the
equilibrium towards the RXR-VDR heterodimer. Nevertheless, a chimeric
version of VDR can induce transcription in response to
1,25(OH)2D3 in the absence of RXR (Lemon and Freedman 1996
), demonstrating that VDR does have intrinsic
transactivation properties. However, in cell-free transcription assays
recently established in our laboratory that are responsive to the
addition of purified VDR, RXR and 1,25(OH)2D3,
transcriptional activation from the OPN VDRE is absolutely dependent on
the addition of both VDR and RXR to the in vitro system; no
activation is observed when either receptor alone is added
(Lemon et al. 1997
). We believe this result definitively
establishes the RXR-VDR heterodimer as the tranactivating complex.
Vitamin D analogues.
We are also studying how potentially important vitamin D analogues that
strongly induce differentiation of myeloid leukemic cells but are not
hypercalcemic may affect the RXR-VDR dimerization status. Using surface
plasmon resonance (BIAcore) in vitro as well as transient transfection
in vivo, we have found that analogues of potential clinical
interest have distinct effects on dimerization, DNA binding, and
ultimately, transactivation relative to 1,25(OH)2D3(Cheskis et al. 1995
). A drawback of this and
other analogue studies has been the use of VDRE from genes that do not
respond during induced differentiation, such as the bone-encoding genes
osteopontin and osteocalcin. The isolation of vitamin D–responsive
genes regulated during myeloid differentiation and subsequent
delineation of their corresponding VDRE, as described below, may
provide much more relevant targets for the assays typically employed
for these analogues (i.e., DNA binding and transcriptional regulation),
as well as shed light on how they may function.
Vitamin D receptor coactivators.
We have used the VDR ligand binding domain (VDRLBD) as an affinity
matrix to identify components of a transcriptionally active nuclear
extract that interact with VDR in response to ligand. We have purified
a complex of at least 10 VDR interacting proteins (DRIPs) ranging from
65 to 250 kDa that associate with the receptor in a strictly
1,25-dihydroxyvitamin D3–dependent manner (Fig. 2
)(Rachez et al. 1998
). These proteins also appear to
interact with other, but not all nuclear receptors such as the thyroid
hormone receptor. The DRIP are distinct from known nuclear receptor
coactivators, although like these coactivators, their interaction also
requires the AF-2 transactivation motif of VDR. In addition, the DRIP
complex contains histone acetyltransferase activity, indicating that at
least one or more of the DRIPs may function at the level of nucleosomal
modification. However, we found that the DRIP selectively enhance the
transcriptional activity of VDR on a naked DNA template utilizing a
cell-free, ligand-dependent transcription assay. Moreover, this
activity can be specifically depleted from the extract by liganded, but
not unliganded, VDRLBD. Overexpression of DRIP100 in vivo resulted in a
strong squelching of VDR transactivation, suggesting the sequestration
of other limiting factors, including components of the DRIP complex.
These results demonstrate the existence of a new complex of novel
functional nuclear receptor coactivators.
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CLONING AND CHARACTERIZATION OF VITAMIN D–INDUCIBLE TARGET GENES |
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TOPABSTRACTFUNCTIONAL AND STRUCTURAL...CLONING AND CHARACTERIZATION OF...REFERENCES |
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1,25(OH)2D3 is a major regulator of mineral
homeostasis and bone formation/remodeling. This ligand can also elicit
potent growth inhibitory and differentiation effects on a variety of
cell types. For example, 1,25(OH)2D3 can induce
normal and leukemic hematopoietic cells to differentiate into cells
displaying characteristics consistent with a more mature
monocyte/macrophage phenotype, including a decrease or cessation in
their proliferation (Abe et al. 1983
, Bar-Shavit et al. 1983
). It is the mechanism of this induced
differentiation that is under consideration.
An examination of the role of 1,25(OH)2D3
during hematopoiesis was prompted by the following two observations:
first, hematopoietic cells contain the vitamin D3 receptor
(VDR) (Mangelsdorf et al. 1984
); and second, osteoclasts
arise from the fusion of circulating mononuclear precursor cells and
therefore represent a terminal stage of mononuclear phagocyte
differentiation. Indeed, Abe and colleagues showed that nanomolar
concentrations of 1,25(OH)2D3 were sufficient
to induce fusion of mouse alveolar macrophages. This same group first
demonstrated that a myeloid leukemic cell line, mouse M1, could be
induced to differentiate along the macrophage lineage by
1,25(OH)2D3 (Abe et al. 1981
).
Subsequently, they and others showed that the human promyelocytic
leukemia cell line HL60 and the human myelomonocytic cell line U937 can
also be induced to terminally differentiate by
1,25(OH)2D3 (Collins et al. 1978
, Ollson et al. 1983
). A variety of other
compounds such as phorbol esters, dimethyl sulfoxide (DMSO) and
retinoic acid also induce the differentiation of these cell lines
(reviewed in Collins et al. 1987
); however, HL-60 cells
differentiate into granulocytes upon exposure to DMSO or retinoic acid
(Collins et al. 1978
, Breitman et al. 1981
), whereas they differentiate into cells exhibiting
distinct monocyte/macrophage characteristics when treated with
1,25(OH)2D3 (McCarty et al.
1983
).
Putative target genes of the vitamin D3 receptor.
Vitamin D-3–inducible effects on cell growth and differentiation ought
to be initiated through the direct activation or repression of target
genes by VDR. The identities of such genes, however, have remained
elusive. Several investigators have reported that a variety of genes
are either up-regulated or down-regulated in myeloid cells in response
to the hormone. Such genes include the cellular oncogenes
c-myc (Grosso and Pitot 1985
, Reistma
et al. 1983
), N-ras, p53, c-fms
(Sariban et al. 1985
) , protein kinase C (Obeid et al. 1990
), and c-jun and junB
(Datta et al. 1991
). None of these genes, however, have
been shown to be direct targets for VDR regulation; more likely, they
represent intermediate or end products of the differentiation process.
We recently reported that the human interleukin-2 gene is
transcriptionally repressed by VDR (Alroy et al. 1995
)
and have preliminary data that the GM-CSF gene is also down-regulated
by the receptor (see below). A recent report describes c-Fos as a
vitamin D3–inducible gene (Candeliere et al. 1996
).
Attempts at directly isolating regulated early genes from HL60 and U937
cells during induced differentiation have been met with limited
success. By applying cDNA subtraction cloning techniques to an HL60
cloned variant cell line called IF10, Bories et al. (1989)
reported the identification of a serine protease called
myeloblastin, whose down-regulation by phorbal esters resulted in
growth arrest of promyelocytic leukemia cells. The same group was also
able to clone by subtraction two related cDNAs encoding fructose 1,6
bisphosphatase (Solomon et al. 1988
). One is activated
by 1,25(OH)2D3 early in HL60 differentiation;
the second is activated by the hormone in peripheral blood monocytes.
It was never established, however, whether induction of fructose 1,6
bisphosphatase is a direct effect of VDR at the level of transcription
initiation or an indirect, downstream effect. Thus, the number of genes
shown to be regulated directly by VDR and the number of characterized
vitamin D response elements remains quite small, making it difficult to
propose accurate models for how VDR recognizes and regulates target
genes, and how those genes induce a biological switch that results in
monocytic-macrophage differentiation.
Differential screening strategy.
Our own strategy has been to isolate and characterize target genes of
VDR that might act as key regulators of differentiation of the
myelomonoblastic U937 cell line. We hypothesized that differentiation
as induced by 1,25(OH)2D3 is mediated by the
combined action of several gene products whose expression is directly
activated transcriptionally by VDR. To isolate putative vitamin
D-3–inducible target genes during myeloid cell differentiation, we
established a differential screen whereby we enriched for genes that
would be among the earliest regulated after addition of ligand. To do
so, we prepared probes by isolating RNA from U937 cells untreated or
treated with 1 x 10-7 mol/L
1,25(OH)2D3 for 4 h. A 4-h pulse of the
ligand was sufficient to commit U937 cells to differentiate along the
monocyte/macrophage pathway. In both the presence (+) and absence (-)
of 1,25(OH)2D3, cycloheximide was included to
prevent further protein synthesis, and 4-thiouridine was added to
enrich for nascent mRNA transcripts using organomercury chromatography;
both strategies were employed to increase the likelihood of an
immediate early transcript induced by 1,25(OH)2D3represented in the probes. In addition, a plasmid cDNA library
was generated from the induced cells (also treated for 4 h with
ligand, cycloheximide, and 4-thiouridine). Approximately 100,000
colonies were replica plated and screened with (-) and (+) probes. An
outline of the differential screening strategy is shown in Figure 3
and described in detail in Rots et al. (1998)
.
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)
and, as described below, this gene constitutes a newly identified
transcriptional target of VDR. The product of this gene inhibits the
cell cycle by blocking key kinases necessary for progression through
G1. Transitions of the cell cycle are controlled by both positive and
negative regulators. Cyclin-dependent kinases (CDK) and their cyclin
partners are the positive factors required for cell cycle progression.
A group of recently characterized small proteins that interact with and
inhibit the activity of cyclin-CDK complexes, called CDK inhibitors
(CKI), act as negative regulators, causing cells to arrest in G1 and
withdraw from the cell cycle (Sherr and Roberts 1995
).
Two families of CKI have thus far been identified: the Cip/Kip family
members, p21Cip1/Waf1,
p27Kip1 and p57Kip2,
share homology at their N-termini, which defines a CDK-interacting
domain, and the Ink4 family, comprised of
p15Ink4b, p16Ink4a,
p18Ink4c and p19Ink4d.
The Ink4 family members contain four tandemly repeated ankyrin repeats
and are structurally unrelated to the Cip/Kip family. Evidence is
accumulating that CKI are targets of extra- and intracellular signals
that regulate cell growth, differentiation and apoptosis. For example,
radiation-induced DNA damage elevates p53 levels, and this protein in
turn transcriptionally induces p21 expression, resulting in cell cycle
arrest (El-Diery et al. 1993
, Harper et al. 1993
). Transforming growth factor-ß acts as an antimitogenic
factor by inducing p15 and/or p27 expression (Polyak et al. 1994
). MyoD up-regulates p21 expression, which is correlated to
muscle cell differentiation (Halevy et al. 1995
).
Finally, several agents that induce myeloid cell differentiation,
including phorbol esters, sodium butyrate, DMSO, and retinoids, as well
as 1,25(OH)2D3, have been shown to up-regulate
p21 and/or p27 expression at the mRNA or protein level (Sherr and Roberts 1995
).
Although we established a strong correlation between vitamin D-3
activation of p21 gene expression and an induction of differentiation,
direct causality was demonstrated by transient overexpression of p21
and/or the related CDK inhibitor p27 in U937 cells in the absence of
1,25(OH)2D3. Ectopic overexpression of these
cell cycle inhibitors resulted in the cell surface
appearance of monocyte/macrophage-specific markers CD11b and CD14
(Liu et al. 1996
), indicating that ligand-modulated
transcriptional activation of a gene encoding a CDK inhibitor directly
results in the induced differentiation of this monoblastic cell line.
However, the extent of U937 differentiation, as assessed by the
induction of CD11b and CD14, was not as great as when
1,25(OH)2D3 was used, suggesting that
additional target genes, encoding other factors that act on terminal
differentiation, are also involved in facilitating the effect.
In fact, other induced candidate target genes identified by our screen,
such as those listed in Table 1
,might also play key roles in carrying out the differentiation program,
separately or in conjunction with p21. Such genes include those
encoding transcription factors involved in growth control and
differentiation, such as the b-zip-HLH protein Mad-1 (Ayer et al. 1993
), and the homeobox protein HoxA10 (Lawrence et al. 1995
, Rots et al. 1998
). HoxA10 protein may
act as general regulator of cell growth because overexpression of
HoxA10 facilitated the differentiation of U937 cells to
monocyte/macrophages independently of 1,25(OH)2D3and acted to strongly inhibit the growth of the breast cancer
cell line MCF-7 by arresting these cells in G1. We hypothesize that
1,25(OH)2D3 causes a coordinate induction of
CDK inhibitors and a number of target gene products such as HoxA10 and
others found in our differential screen. The induction of this entire
set of genes would lead to full cell cycle arrest and subsequent
monocyte/macrophage differentiation. We are currently defining the
roles of these newly identified VDR target genes during
1,25(OH)2D3-induced growth inhibition and
differentiation, as well as examining a possible cooperative action of
CDK inhibitors and the other target genes in mediating these effects.
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Induction of p21 mRNA occurs within 2 h of
1,25(OH)2D3 addition; this induction is
cycloheximide resistant, suggesting that it is a direct effect of
liganded VDR (i.e., a transcriptional response). The expression of
other CDK inhibitors, such as p27Kip1 and the
Ink4 family members p15, p16 and p18, were also found to be induced by
the ligand. Using a p21 promoter-reporter construct, we demonstrated
that the p21 gene is transcriptionally activated by
1,25(OH)2D3 in a VDR-dependent, but
p53-independent manner, and we found a functional vitamin D response
element within the p21 promoter at -770 that mediates this induction
(Liu et al. 1996
). Upon DNaseI footprint analysis of the
p21 promoter with purified VDR and RXR, we recently observed at least
four protected regions spanning from -565 to -822, including the
original VDRE we reported at -770. Gel shift analysis with the
footprinting probe is consistent with the notion that there are
multiple VDR-RXR binding sites within the p21 promoter because it
confers four or five shifted complexes. Deletion of any one of these
sites abolishes responsiveness of the promoter to
1,25(OH)2D3 (Fig. 4
),suggesting a complex, cooperative set of interactions by VDR-RXR, in
which all of the receptor binding sites are required intact for
transcriptional activation to occur.
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FOOTNOTES |
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2 Supported by grants from the National Institutes
of Health and the Human Frontiers Science Program. L.P.F. is a Scholar
of the Leukemia Society of America.
3 Abbreviations used: CDK, cyclin-dependent
kinases; CKI, CDK inhibitors; DMSO, dimethyl sulfoxide; DRIP, vitamin D
receptor interacting proteins; LBD, ligand-binding domain; OPN,
osteopontin gene; RA, retinoic acid; RXR, retinoid-X
receptor; RXRE, RXR-response element; SPR, surface plasmon resonance;
VDR, vitamin D3 receptor; VDRE, VDR-response element;
VDRLBD, VDR ligand binding domain.
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TOPABSTRACTFUNCTIONAL AND STRUCTURAL...CLONING AND CHARACTERIZATION OF...REFERENCES |
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