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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2683-2690
NEOPLASIA
From the Division of Hematology/Oncology, Department of Medicine,
University of Pittsburgh Medical Center, and the University of
Pittsburgh Cancer Institute, Pittsburgh Pennsylvania; and the
Department of Pharmacology and Molecular Toxicology, University of
Massachusetts Medical School, Worcester, Massachusetts.
The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the
genes for nucleophosmin (NPM) and the retinoic acid receptor alpha
(RAR
Acute promyelocytic leukemia (APL, FAB M3) is
characterized by a rearrangement of 1 allele of the retinoic acid
receptor alpha (RAR The t(15;17) reciprocal chromosomal translocation that is found in
leukemic cells from over 95% of patients with APL introduces downstream elements of the RAR Strong evidence indicates that expression of the PML-RAR fusion protein
produces the APL phenotype.9-12 However, there is much
controversy over the molecular mechanism by which PML-RAR alters
myeloid growth and differentiation. PML-RAR retains the RAR Alternative hypotheses have also been put forward. PML-RAR contains the
dimerization domains of wild-type RAR One approach toward reconciling these seemingly disparate hypotheses is
to study the rare variants of APL that do not express the PML-RAR
fusion protein. The first such variant to be characterized was the
t(11;17) of which 6 cases have been described
worldwide.22,23 Blasts with the t(11;17) genotype, though,
differ phenotypically from t(15;17) blasts, and do not differentiate
when exposed to all-trans retinoic acid. It has been proposed
that this phenotypic difference could be explained by the finding that
the PLZF-RAR fusion product of t(11;17) is a less potent
transcriptional activator than PML-RAR.24,25 This concept
is further supported by recent studies indicating that PLZF-RAR forms
more stable interactions with co-repressor molecules.18
Our group has characterized the t(5;17) variant, of which 3 cases have
been identified.26,27 The t(5;17) blasts are
morphologically similar to t(15;17) cells. Furthermore, like t(15;17),
t(5;17) leukemic cells differentiate in vitro when cultured with
all-trans retinoic acid.28 These phenotypic
similarities make t(5;17) an important model system in which to
identify common molecular pathways that underlie APL.
The t(5;17) chromosomal rearrangement translocates the genomic loci for
the nucleolar phosphoprotein nucleophosmin (NPM) and RAR We characterize the ability of the NPM-RAR proteins to act as
ligand-dependent transcriptional activators. We demonstrate that
NPM-RAR-mediated transcriptional activation differs from wild-type
RAR Cell culture and transfection protocols
CV1.
CV1 cells were obtained from the American Type Culture Collection
(ATCC; Bethesda, MD), and maintained in a humidified 5% CO2 atmosphere in Dulbecco's modified Eagle's medium
(DMEM; Mediatech, Herndon, VA) supplemented with glutamine, pen/strep,
and 10% fetal bovine serum (FBS) (GIBCO, Grand Island, NY). Sixteen
hours prior to transfection, 2 × 105 cells were
replated in 6-well dishes with media containing delipidated FBS
(Cocalico Biologicals, Reamstown, PA). Cells were transfected using
Lipofectamine (GIBCO) and OptiMem serum-free media (GIBCO) according to
the manufacturer's protocol; after 5 hours of incubation with the
lipofectamine-DNA complexes, the media was readjusted to 10%
delipidated FBS containing 1 µM all-trans retinoic acid (Sigma, St. Louis, MO) or an equal volume of ethanol vehicle. Transfection mixes contained 625 ng of chloramphenical acetyl transferase (CAT)-reporter plasmid, 125 ng of test transcriptional activator, pBluescript II KS as carrier, and 100 ng of RSV-luciferase as a transfection control.
HeLa.
HeLa cells were obtained from the ATCC. The cells were grown under the
same conditions as CV1 cells. Sixteen hours before transfection, cells
were plated in delipidated medium. Cells were transfected by
coprecipitation of CaPO4-DNA complexes.29 Six hours after application of the DNA precipitates, the cells were washed
and fresh delipidated medium containing 1 µM retinoic acid or ethanol
vehicle was added.
K562.
K562 cells were obtained from the ATCC. Cells were grown in RPMI 1640 (Mediatech) supplemented with glutamine, pen/strep, and 10% FBS.
Sixteen hours prior to transfection cells were washed and plated in
RPMI containing 10% delipidated FBS. K562 cells were electroporated
using a Gene Pulser (Bio-Rad, Hercules, CA) at 270 mV and 960 µF.
107 cells were transfected with a total of 20 µg of CAT
reporter plasmid, transcriptional activator expression vector, RSV-luciferase, and carrier DNA in the same molar ratios as for
the CV1 and HeLa transfections. Ater transfection the cells were
incubated on ice for 15 minutes and plated in delipidated medium
containing 1 µM retinoic acid or ethanol vehicle.
U937.
U937 cells were obtained from the ATCC. Culture and electroporation
conditions were the same as for K562 cells.
Luciferase and CAT assays
Electrophoretic mobility shift assays
Coprecipitation The coding sequence for NPMS-RAR was subcloned into a malE expression vector (New England Biolabs, Beverly, MA) in the appropriate reading frame to encode a maltose-binding protein (MBP) fusion. MBP-NPMS-RAR or control MBP protein was affinity-purified from bacterial lysates using amylose resin. 30 µg malE-fusion protein and 20 µL of 35S-methionine-programmed reticulocyte lysate were mixed for 4 hours at 4°C in 20 mmol/L Tris pH8, 110 mmol/L NaCl, 1 mmol/L EDTA, and 0.5% NP-40, and then allowed to bind to amylose resin. After extensive washing, the resin was boiled and the eluted products subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The gels were dried and imaged by autoradiography.Co-immunoprecipitation Programmed reticulocyte lysate (10 µL) was mixed at 4°C in 20 mmol/L Hepes pH 7.9, 50 mmol/L NaCl, 1 mmol/L EDTA, 5% glycerol, 0.05% Triton X-100, and 0.5% bovine serum albumin, and then incubated with 1 µg antibody (either anti-RXR rabbit polyclonal
[Santa Cruz Biotechnology, Santa Cruz, CA] or anti-RAR rabbit
polyclonal [Santa Cruz Biotechnology]) for an additional 16 hours.
Complexes were precipitated with Protein A-sepharose (Pharmacia,
Piscataway, NJ), washed, boiled, and fractionated by SDS-PAGE. After
electrophoresis, the gel was dried and imaged by autoradiography.
Far-Western analysis Far-Western blot analysis was conducted as described.33 Bacterially expressed GST-fusion proteins were purified using glutathione agarose beads and separated in SDS-PAGE. Proteins were transferred onto nitrocellulose membrane in 25 mM Tris-HCl, pH 8.3, 192 mM glycine, 0.01% SDS. The bound proteins were denatured in 6 mol/L guanidine hydrochloride (GnHCl), and renatured by stepwise dilution of GnHCl in hybridization buffer (25 mM Hepes pH 7.7, 25 mM NaCl, 5 mM MgCl2, 1 mM DTT). The filters were blocked overnight with 5% nonfat milk in the hybridization buffer followed by a rinse in 1% nonfat milk plus 0.05% NP-40. In vitro translated 35S-methionine labeled proteins generated in reticulocyte lysate (Promega) were hybridized to the immobilized proteins overnight in 20 mM Hepes, pH 7.7, 75 mM KCl, 0.1 mM EDTA, 2.5 mM MgCl2, 0.05% NP-40, 1% milk, 1 mM DTT. After hybridization, the membrane was washed 3 times with hybridization buffer and the bound probe was detected by autoradiography.
NPM-RAR acts as a retinoic acid-dependent transcriptional activator Preliminary observations indicated that NPMS-RAR and NPML-RAR are able to activate transcription of an mRAR 2-CAT reporter construct in a ligand-dependent
fashion.27 We sought to determine whether such
ligand-dependent transcriptional activation shows similar promoter and
cell specificity as has been reported for PML-RAR.7,8,14 We
compared the ability of NPMS-RAR, NPML-RAR, PML-RAR, and RAR to activate transcription of a series of retinoic acid-dependent reporter plasmids in CV1 monkey kidney cells, HeLa human cervical carcinoma cells, and K562 human myeloid leukemia cells.
As reporter constructs 2 artificial RAREs (TREp-CAT34 and
[TRE3]3-TK-CAT35), and 4 naturally occurring retinoic
acid responsive promoters (mRAR 2-CAT containing 3.75 kb upstream to the mRAR 2 cap site,36,37 mRAR 2-CAT containing 1.3 kb
of promoter and 5'-untranslated sequence of
mRAR 2,38 CRABP-II CAT containing 2.5 kb of CRABP-II
promoter,39 and CRBP-I CAT containing 2027 bases upstream
to the transcriptional start site of CRBP-I36) were used.
The graphs of Figure 1 present the ratio of
CAT activity (normalized for transfection efficiency) from transfected
cells incubated with retinoic acid compared with the ethanol control. CRBP-I CAT data are not presented in the analysis of K562 cells because
the CAT activities were not significantly different from the no-lysate
negative control.
NPM-RARs form homodimers In vitro interactions of the NPM-RARs with a target RARE were assessed in an electrophoretic mobility shift assay (EMSA). Figure 2 indicates that NPMS-RAR and NPML-RAR bind and retard the migration of a radiolabeled RARE. This was observed both with NPM-RAR proteins derived from in vitro translation (Figure 2A) or with affinity purified MBP-NPM-RAR protein (Figure 2C). The specificity of this reaction is documented by the competition reaction using cold RARE (Figure 2B and data not shown). The RAR oligonucleotide contains a direct repeat of 2 consensus half-sites30,31; binding of NPM-RAR to this site
led us to question whether the NPM-RAR fusion proteins might interact
with DNA as a homodimer. To directly test the ability of NPM-RAR to
homodimerize in solution, we incubated MBP-NPMS-RAR with in
vitro translated 35S-NPMS-RAR protein, and captured the
complexes using amylose resin (Figure 3).
Recovery of the radiolabeled NPMS-RAR with
MBP-NPMS-RAR, but not the MBP control, indicates that
NPMS-RAR is able to form homodimers in solution.
NPM-RAR can heterodimerize with RXR Because the NPM-RAR fusion proteins contain the heterodimerization domains of RAR , it is reasonable to postulate that they might form
heterodimers with RXR. To determine whether NPM-RAR can form
heterodimers as well as homodimers, we incubated in vitro translated
radiolabeled RXR with soluble MBP-NPMS-RAR, and captured the complexes with amylose resin. Figure 4A
indicates that MBP-NPMS-RAR, but not control MBP protein,
is able to form a stable complex with RXR. To confirm this data, we
tested whether in vitro translated NPMS-RAR and RXR would associate in
a complex that could be immunoprecipitated by antibodies to either
constituent. Figures 4B and 4C indicate that NPMS-RAR and
RXR proteins form a stable heterodimer complex that can be precipitated
with either anti-RAR or anti-RXR antisera. Furthermore, co-transfection
of RXR with NPMS-RAR or NPML-RAR increased
ligand-inducible activation of an RARE-reporter construct (data not
shown).
NPM-RAR acts as a dominant-negative inhibitor of RAR , similar
to what has been described for PML-RAR.7,13 To further investigate this possibility, we assessed the ability of co-transfected NPMS-RAR or PML-RAR to modulate RAR function. Both
NPMS-RAR and PML-RAR suppressed the level of retinoic
acid-induced activation of an RARE-reporter construct (Figure
6). This indicates that like PML-RAR,
NPMS-RAR can act as a dominant-negative inhibitor of
RAR .
NPM-RAR interaction with nuclear receptor co-repressor and co-activator proteins Transcriptional repression and activation by RAR is mediated
through ligand-dependent recruitment of co-repressor or co-activator complexes (see review by Redner et al41). In the absence of retinoic acid, RAR binds directly to the co-repressor molecules SMRT
or N-CoR. In the presence of retinoic acid, RAR releases the
co-repressor complex and binds a receptor-associated co-activator protein (RAC33,42), which itself recruits other
co-activator proteins.33 We used Far-Western analysis to
assess the interactions of NPM-RAR with the co-repressor
SMRTe43 and the co-activator RAC3.42 The
specific activity of the probes were all similar and identical exposure
times used. In the absence of ligand, wild-type RAR and both NPM-RAR
and PML-RAR interact efficiently with C-SMRT (corresponding to AA
1993-2507 of hSMRTe), suggesting that the fusion proteins are not
defective in co-repressor association (Figure
7). As expected, unliganded RAR and the
RAR fusion proteins fail to interact with the co-activator RAC3 in the
absence of ligand.
We have previously identified 2 alternatively spliced forms of
NPM-RAR that are expressed as a result of the t(5;17) translocation in
APL.27 Both contain the DNA binding, dimerization, ligand binding, and C-terminal activation domains of RAR
pSG5-hRAR
Submitted October 28, 1998; accepted December 20, 1999.
Supported by National Institutes of Health Grant No. R29 CA67346 (R.L.R.), the American Institute for Cancer Research Grant No. 96B057 (R.L.R.), and American Cancer Society Grant No. 98-085-01-LBC (J.D.C.).
Reprints: Robert L. Redner, E1058 Biomedical Science Tower, University of Pittsburgh Medical Center, 211 Lothrop St, Pittsburgh, PA 15213; e-mail: redner+{at}pitt.edu.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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