|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
NEOPLASIA
From the Department of Medicine, Division of
Experimental Medicine, Lady Davis Institute for Medical Research, Sir
Mortimer B. Davis Jewish General Hospital, McGill University, Montreal,
Quebec, Canada; and the Cell Biology Program, Memorial Sloan-Kettering
Cancer Center, Sloan-Kettering Division, Graduate School of Medical
Sciences, Cornell University, New York, NY.
Retinoic acid (RA) signaling is mediated by its nuclear
receptors RXR and RAR, which bind to their cognate response elements as
a heterodimer, RXR/RAR, and act in concert with coregulatory factors to
regulate gene transcription on ligand binding. To identify specific
cofactors that interact with the RXR/RAR heterodimer in acute
promyelocytic leukemia (APL) cells, a double cistronic construct was
used that allowed coexpression of the RXR LBD (ligand binding domain)
with the RAR LBD as an affinity matrix to pull down interacting
proteins from nuclear extracts prepared from a human APL cell line,
NB4. A group of proteins was detected whose interaction with RXR/RAR is
ligand inducible. The molecular weight pattern of these proteins is
similar to that of a complex of proteins previously identified as DRIP
or TRAP, which are ligand-dependent transcription activators of VDR and
TR, respectively. The RXR/RAR-interacting proteins from NB4 were
confirmed to be identical to the DRIP subunits by comparative
electrophoresis, Western blot analysis, and in vitro protein
interaction assay. In addition to RXR/RAR, the DRIP component can
interact directly with the APL-specific PML-RAR Retinoids are a group of natural and synthetic
derivatives of vitamin A that exert a wide variety of effects on
biologic processes, such as homeostasis, pattern formation during
embryogenesis, and cellular growth and differentiation.1,2
Retinoid signaling is mediated by 2 nuclear receptors Although the precise mechanisms by which nuclear receptors regulate
gene transcription are unknown, they have been shown to interact
directly with components of the basal transcription machinery, perhaps
affecting its assembly or function.7-9 Additionally, recent studies have identified a group of nuclear receptor-interacting proteins that are specific coregulatory factors in mediating gene transcription. Coactivators interact with nuclear receptors in a
ligand-inducible manner and require the integrity of the AF-2 domain.
Identified coactivators include members of the SRC-1 family (SRC-1/NCoA-1/p160,10-12
ACTR/pCIP/RAC-3/AIB,13-15 and
TIF-2/NCoA-2/GRIP-1)16,17; the cointegrators CBP/p300 and
their interacting protein pCAF18,19; other factors
including RIP140,20,21 SUG-1/TRIP-1,22,23 TIF-1,24 and ARA70.25 Discoveries
of histone acetyltransferase activity in CBP/p300, pCAF, and some
members of the SRC-1 family suggest that coactivators may function
through chromatin structural modifications that allow promoter
accessibility for the preinitiation complex, leading to the activation
of transcription.26-29 Interestingly, 2 identified
receptor corepressors, SMRT and NCo-R,30-32 appear to
modify chromatin structure by recruiting histone deacetylases and to
repress transcription in the absence of ligand.33,34
A distinct coactivator complex was identified recently by 2 separate
groups for its ligand-dependent interaction to the vitamin D3 receptor (DRIP) or to the thyroid hormone receptor
(TRAP).35,36 DRIP/TRAP exists as a large macromolecular
complex containing at least 15 proteins that comprise a novel set of
nuclear receptor coactivators. In vitro transcription assays using
either crude cell nuclear extracts or purified components of the
general transcription complex suggested that the DRIP/TRAP complex acts
as a ligand-dependent positive transcriptional regulator of various
nuclear receptors.35,36
Hormonal therapies targeting nuclear receptors are frequently used in
the treatment of neoplastic diseases. In acute promyelocytic leukemia
(APL), retinoic acid (RA) has been demonstrated to have a dramatic
effect on the induction of cytodifferentiation and the maturation of
leukemic cells, leading to clinical remission in
patients.37-41 APL is characterized by a reciprocal
chromosomal translocation, t(15;17), that fuses the PML gene with the
retinoic acid receptor We have reported that one such retinoid-resistant subclone of NB4, R4,
harbors a dominant-negative PML-RAR We report here the detection of a protein complex in NB4 that
interacted with the RXR/RAR heterodimer in a ligand-inducible manner.
The complex is virtually identical to a previously identified transcription coactivator complex, known as DRIP or TRAP, for its
interaction with VDR and TR, dependent on their respective ligands.35,36 The same complex is also present in 3 RA-resistant NB4 subclones, in U937 subclones that express different
levels of PML-RAR Cell culture
Purification of GST fusion proteins
Nuclear extract preparation Nuclear extracts were prepared according to the Dignam method.61 Prepared nuclear extracts were then dialyzed twice against 100-fold excess volume of dialysis buffer (100 mmol/L KCl, 20 mmol/L HEPES-KOH [pH 7.9], 0.2 mmol/L EDTA, 20% glycerol, 1 mmol/L dithiothreitol) for 2 hours each time at 4°C. Extract amounts were measured by Bradford assay (Bio-Rad), and the extracts were stored in aliquots at 80°C.
In vitro GST pull-down assay Immobilized GST fusion proteins (10-20 µg) were preincubated at 4°C for 1 hour with or without ligand in the binding buffer (20 mmol/L HEPES-KOH [pH 7.9], 180 mmol/L KCl, 0.2 mmol/L EDTA, 0.05% NP-40, 0.5 mmol/L phenylmethylsulfonyl fluoride, 1 mmol/L dithiothreitol) containing 1 mg/mL bovine serum albumin. The fusion proteins were then incubated with either 1.2 mg nuclear extracts or 500 000 cpm 35S-labeled in vitro translated protein (TNT Coupled Reticulocyte Lysate System; Promega, Madison, WI) with or without ligand in the binding buffer at 4°C for 4 to 5 hours. Sepharose beads were then washed 3 times with the binding buffer containing 0.1% NP-40. For isolation of the protein complex, the bound proteins were eluted with washing buffer containing 0.2% N-lauroyl sarkosine, separated by SDS-PAGE, and visualized by silver nitrate staining (Bio-Rad). For in vitro translated proteins, the Sepharose beads were boiled in SDS-sample buffer, and proteins were separated by SDS-PAGE and analyzed by autoradiography.Western analysis Proteins eluted from the glutathione-Sepharose matrix were analyzed by SDS-PAGE and transferred to a nitrocellulose membrane (Bio-Rad). Primary antibodies were made 1:1000 dilution in 5% milk in phosphate-buffered saline, and proteins that interacted with the antibodies were detected using the ECL Western blotting detection kit (Amersham, Buckinghamshire, UK).
Proteins interact with retinoid receptors in a ligand-dependent manner in NB4 cells To isolate specific cofactors that interact with the retinoid receptors in APL cells, we overexpressed the retinoid receptor heterodimer ligand-binding domain using a double cistronic expression construct (Figure 1A) in which the RXR LBD was fused to glutathione-S-transferase (GST) and the RAR LBD was tagged with 6 histidine residues.60 The ribosome-binding site preceding each cistron allows the coexpression of both proteins in the form of a heterodimer. The nuclear receptor LBD consists of a transcriptional activation domain AF-2, which is essential for interaction with coactivators. Nuclear extracts prepared from NB4 cells were passed through immobilized GST-RXR LBD/RAR LBD in the absence or presence of 5 µmol/L t-RA. As a result, we isolated a group of proteins consisting of at least 10 subunits, ranging in molecular weight from 77 to 250 kd, that interacted specifically with the retinoid receptor heterodimer only when ligand was present (Figure 1B, lane 3). In contrast, in the absence of ligand or with GST alone, few nonspecific binding proteins were observed (Figure 1B, lanes 1, 2).
As demonstrated above, t-RA appeared to induce the interaction of a specific protein complex to the RXR/RAR heterodimer. Because t-RA in vitro only binds to and activates RAR, we asked whether RXR binding could also be involved in the recruitment of the protein complex by using a synthetic RXR-selective agonist LG100153. Protein interactions were examined with the immobilized RXR LBD/RAR LBD in the presence of LG100153 (Figure 1C, lane 3) and compared with t-RA and a synthetic RAR-specific agonist, LG100272 (TTNPB) (lanes 2, 4); 1 µmol/L of the ligand was used to minimize cross-reactivity. Both selective agonists have been characterized; they have been reported to bind their respective receptors with high affinity and to transactivate selectively the reporter constructs on the respective response elements at this concentration.62-64 Figure 1C shows that t-RA and LG100272 equally induce the binding of the complex to receptor, whereas LG100153 has no effect. This suggests that the ligand-dependent interaction of the protein complex is mediated through the RAR partner of the retinoid receptor heterodimer. Further, we found that binding to RAR of an antagonistic ligand LG100815 did not recruit the protein complex (data not shown), suggesting that conformational changes associated with transcriptional activation are required for binding of the protein complex. Retinoid receptor heterodimer interacts with the DRIP/TRAP complex To identify proteins in the RAR/RXR-interacting complex, we performed immunoblot analyses with antibodies to known nuclear receptor coactivators. Anti-CBP, ACTR, and SRC-1 did not react with any of the proteins pulled down from NB4 extracts (data not shown). However, the distribution of these proteins by apparent molecular weight was similar to a recently identified coactivator complex, DRIP or TRAP, that shows ligand-dependent interactions with VDR and TR. To determine whether the protein complex we isolated from APL NB4 cells included proteins within the DRIP complex, we took several approaches. First, a GST pull-down assay was performed with immobilized VDR LBD, compared with the RXR LBD/RAR LBD heterodimer in the absence or presence of their respective ligands, 1,25-dihydroxy vitamin D3 (VD3) and t-RA. As shown in Figure 2A, an essentially identical group of interacting proteins was observed with liganded VDR LBD (lane 2) and RXR LBD/RAR LBD (lane 4). To confirm the identity of individual proteins, we obtained polyclonal antibodies to 2 members of the DRIP complex.65 Immunoblot analyses with antibodies to DRIP130 and DRIP150 confirmed their presence in the retinoid receptor-interacting proteins pulled down from NB4. Both antibodies recognized specific protein bands at their corresponding molecular weights only in the presence of t-RA (Figure 2B, lanes 3, 6).
Since previous reports identified DRIP205/TRAP220 as the subunit within
the complex that interacts directly with VDR and TR,65-67 we assessed whether DRIP205 could interact with the RXR/RAR
heterodimer. 35S-labeled DRIP205 protein prepared by in
vitro translation was allowed to bind RXR LBD/RAR LBD, and a
significant ligand-dependent interaction was observed (Figure 2C, lanes
4, 5). Increasing the t-RA concentration from 1 µmol/L to 10 µmol/L
did not further enhance the binding, suggesting that the interaction at
1 µmol/L already reached its maximum. Consistent with the earlier
report, DRIP205 showed increased binding to VDR in the presence of its ligand VD3 (lanes 7, 8). We also examined the binding of
DRIP205 to APL-specific fusion protein PML-RAR Given the identity by apparent molecular weight of the complex binding to RXR/RAR and to VDR, the identification of 2 DRIP subunits for which specific antibodies were available, and the observation that DRIP205 could bind directly with the liganded retinoid receptor, we concluded that the RXR/RAR-interacting proteins isolated from NB4 cells were identical to those in the DRIP/TRAP complex. Identical DRIP complex is present in RA-resistant APL cell lines Because several RA-resistant cell lines display altered interactions between their retinoid receptors and cofactors in the presence of t-RA,55 we asked whether the particular DRIP complex isolated from NB4 cells was also present in its RA-resistant subclones. Protein complex interactions with the RXR/RAR in 3 resistant subclones R4, MR6, and MR2were compared to those in NB4. Figure
3 shows an identical pattern of
t-RA-dependent interacting proteins in all 4 cell lines examined
(lanes 3, 5, 7, 9). To examine whether the DRIP complexes isolated from
the resistant clones have altered affinity to retinoid receptors in
comparison with NB4 cells, we reduced the concentration of t-RA in the
binding assay to 100 nmol/L and still obtained an identical pattern of
interaction in all cell lines (data not shown). This finding suggests
that these RA-resistant cell lines maintain normal DRIP complexes that interact with retinoid receptors in a ligand-dependent manner. Thus,
abnormalities in either expression or function of the protein components within the DRIP complex do not appear to account for the RA
unresponsiveness in these resistant APL cells.
Expression of the PML-RAR  gene plays a dual role in the phenotype of
APL: it blocks cytodifferentiation at physiologic levels of RA but
responds to pharmacologic concentrations of RA. The myeloid precursor
U937 cell line differentiates poorly in response to RA; however, when
stably expressing PML-RAR, these cells show increased sensitivity to
RA-induced differentiation.68 To determine whether
expression of the PML-RAR fusion protein affects either the
expression of the DRIP components or their interaction with retinoid
receptors, we compared the interaction between the DRIP complex and the
retinoid receptors in U937 clones that differ in their PML-RAR
expression. U937/PR9 is a subclone stably transfected with PML-RAR
under the control of a Zn2+-inducible promoter, so that
high levels of PML-RAR could be induced in these cells by treatment
with ZnSO4. We measured the PML-RAR protein levels in
U937/PR9 cells with or without the induction by 100 µmol/L
ZnSO4 for 24 hours and compared them with those of natural
PML-RAR-expressing NB4 and a U937/SN4 subclone transfected with
vector alone (Figure 4A). NB4 expressed
PML-RAR, whereas U937/SN4 did not (lanes 1, 2). U937/PR9 cells
without Zn2+ induction had a low level of PML-RAR
expression, which could be greatly induced by the treatment of 100 µmol/L ZnSO4 (lanes 3, 4). All cell lines examined
expressed equal levels of RAR. When the binding of the DRIP complex
to RXR/RAR in these cells was examined, we found that all cells
displayed identical ligand-dependent DRIP interaction to the receptors
regardless of their PML-RAR expression levels (Figure 4B, lanes 7, 9, 11). These observations suggest that induced expression of the
oncoprotein PML-RAR does not alter the expression or repress the
function of the DRIP components. Furthermore, consistent with our
findings in the RA-resistant APL cell lines, U937 clones with different
sensitivity to RA have identical patterns of ligand-dependent
DRIP binding.
The PML-RAR We extended our analysis to other non-APL cancer cell lines, including myelocytic leukemia cell lines HL-60 (Figure 4B, lanes 4, 5) and KG-1, the Namalwa B-cell line, and the breast cancer cell line MDA231. We found that KG-1, Namalwa B cells, and MDA231 all exhibited the same RXR/RAR-interacting complex as observed in NB4 cells (data not shown). Initially, HL-60 cells did not show the receptor interaction of the 3 high-molecular-weight protein components at 205, 240, and 250 kd, respectively (Figure 4B). However, when higher concentrations of protease inhibitors were used in the preparation of HL-60 nuclear extract, a separate GST pull-down experiment detected the DRIP205 subunit within the complex (data not shown). Northern analysis also revealed that HL-60 expressed all 3 genes at levels similar to those of NB4 (data not shown).
Great efforts have been made in recent years to understand the
diverse functions of nuclear receptors. Crystallography studies of
several nuclear receptors' LBD structures and discoveries of various
receptor coregulatory factors have brought insights to these complex
hormonal signaling pathways.69-73 We report here the
isolation of a group of distinct proteins from APL NB4 cells that
interact with the LBD of the retinoid receptor heterodimer in a
ligand-dependent manner. As shown by receptor-selective ligands, the
interaction of this complex is mediated through RAR, not RXR (Figure
1). The proteins in the complex are identified as virtually identical
to those in the coactivator complex DRIP/TRAP on the basis of
comparative electrophoresis, immunoblot analyses, and a direct
protein-protein interaction assay (Figure 2). Expression of the
APL-specific oncoprotein PML-RAR Our immunoblot analyses with antibodies to known coactivators, including SRC-1, ACTR, and CBP, did not identify them among the DRIP proteins. This is consistent with the sequencing data on the DRIP subunits, whose coding sequences share little homology with the SRC-1 family of the coactivators and thus belong to a distinct family of coactivators. Indeed, a recent report by Treuter and coworkers67 showed that the DRIP205/TRAP220 subunit competes with the SRC-1 family of coactivators and with CBP for binding to the nuclear receptors and that their binding to the receptor LBD AF-2 domain is mutually exclusive. We found the ubiquitous presence of the DRIP complex in all tested
resistant APL clones and in several non-APL cancer cell lines, varying
from leukemia cells to breast cancer cells. Our results show that 3 APL
clones that have lost transcription and differentiation responses to RA
retain the same DRIP complex as NB4 and exhibit functional
ligand-dependent association of the complex to the receptor at
concentrations of t-RA as low as 100 nmol/L (Figure 3; data not shown).
Because these cells are resistant to more than 100-fold higher
concentrations of t-RA, these data strongly suggest that reduced
affinity of DRIP/TRAP to retinoid receptors is not the cause of RA
resistance in these cells. In accordance with this finding, when U937
cells that differentiate poorly in response to RA are induced to
respond by the expression of PML-RAR
We thank Dr Ronald M. Evans for providing the bicistronic RXR/RAR
expression vector, Dr Richard L. Momparler for 1,25-dihydroxy vitamin
D3 ligand, Dr Reid Bissonnette (Ligand Pharmaceuticals) for
RXR- and RAR-selective ligands, Dr Pierre Chambon for the anti-RAR
Submitted September 2, 1999; accepted May 15, 2000.
Supported by a grant from the Medical Research Council of Canada (MRC). W.S. was supported by an MRC Studentship Award, and W.H.M. is a Scholar of the MRC.
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.
Reprints: Wilson H. Miller Jr, 3755 Chemin de la Cote-Ste-Catherine, Montreal, Quebec, Canada H3T 1E2.
1. De Luca LM. Retinoids and their receptors in differentiation, embryogenesis, and neoplasia. FASEB J. 1991;5:2924-2933[Abstract]. 2. Gudas LJ, Sporn MB, Roberts AB. Cellular biology and biochemistry of the retinoids. In: Sporn MB,Roberts AB,Goodman DS, eds. The Retinoids: Biology, Chemistry, and Medicine. New York, NY: Raven Press; 1994:443-520.
3.
Allenby G, Bocquel MT, Saunders M, et al.
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs): interactions with endogenous retinoic acids.
Proc Natl Acad Sci U S A.
1993;90:30-34 4. Leid M, Kastner P, Durand B, et al. Retinoic acid signal transduction pathways. [Review]. Ann N Y Acad Sci. 1993;684:19-34[Abstract].
5.
Mangelsdorf DJ, Thummel C, Beato M, et al.
The nuclear receptor superfamily
6.
Kastner P, Mark M, Chambon P.
Nonsteroid nuclear receptors 7. Jacq X, Brou C, Lutz Y, et al. Human TAFII30 is present in a distinct TFIID complex and is required for transcriptional activation by the estrogen receptor. Cell. 1994;79:107-117[Medline] [Order article via Infotrieve].
8.
Schulman IG, Chakravarti D, Juguilon H, Romo A, Evans RM.
Interaction between the retinoid X receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation.
Proc Natl Acad Sci U S A.
1995;92:8288-8292 9. May M, Mengus G, Lavigne A, Chambon P, Davidson I. Human TATII28 promotes transcriptional stimulation by activation function 2 of the retinoid X receptors. EMBO J. 1996;15:3093-3104[Medline] [Order article via Infotrieve].
10.
Onate S, Tsai S, Tsai M, O'Malley B.
Sequence and characterization of a coactivator for the steroid hormone receptor superfamily.
Science.
1995;270:1354-1357 11. Takeshita A, Yen PM, Misiti S, et al. Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator. Endocrinology. 1996;137:3594-3597[Abstract]. 12. Torchia J, Rose DW, Inostroza J, et al. The transcriptional coactivator p/CIP binds CBP and mediates nuclear-receptor function. Nature. 1997;387:677-684[Medline] [Order article via Infotrieve]. 13. Chen H, Lin RJ, Schiltz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997;90:569-580[Medline] [Order article via Infotrieve].
14.
Li H, Gomes PJ, Chen JD.
RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2.
Proc Natl Acad Sci U S A.
1997;94:8479-8484
15.
Anzick SL, Kononen J, Walker RL, et al.
AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer.
Science.
1997;277:965-968 16. Voegel JJ, Heine MJS, Zechel C, Chambon P, Gronemeyer H. TIF2, a 160 KDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996;15:3667-3675[Medline] [Order article via Infotrieve]. 17. Hong H, Kohli K, Garabedian MJ, Stallcup MR. GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol. 1997;17:2735-2744[Abstract].
18.
Hanstein B, Eckner R, DiRenzo J, et al.
p300 is a component of an estrogen receptor coactivator complex.
Proc Natl Acad Sci U S A.
1996;93:11540-11545 19. Kamei Y, Xu L, Heinzel T, et al. A CBP-integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996;85:403-414[Medline] [Order article via Infotrieve]. 20. Cavailles V, Dauvois S, L'Horset F, et al. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995;14:3741-3751[Medline] [Order article via Infotrieve].
21.
Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson J.
A regulatory role for RIP140 nuclear receptor activation.
Mol Endocrinol.
1998;12:864-881 22. Lee JW, Ryan F, Swaffield JC, Johnson SA, Moore DD. Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature. 1995;374:91-94[Medline] [Order article via Infotrieve]. 23. Baur Ev, Zechel C, Heery D, et al. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J. 1996;15:110-124[Medline] [Order article via Infotrieve]. 24. Le Douarin B, Zechel C, Garnier J, et al. The N-terminal part of TIF1, a putative mediator of the ligand dependent activation function (AF-2) of nuclear receptors, is fused to B-Raf in the oncogenic protein T18. EMBO J. 1995;14:2020-2033[Medline] [Order article via Infotrieve].
25.
Yeh S, Chang C.
Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.
Proc Natl Acad Sci U S A.
1996;93:5517-5521 26. Ogryzko V, Schlitz R, Russanova V, Howard B, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87:953-959[Medline] [Order article via Infotrieve]. 27. Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature. 1996;384:641-643[Medline] [Order article via Infotrieve]. 28. Spencer TE, Jenster G, Burcin MM, et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997;389:194-198[Medline] [Order article via Infotrieve]. 29. Martinez-Balbas M, Bannister AJ, Martin K, et al. The acetyltransferase activity of CBP stimulates transcription. EMBO J. 1998;17:2886-2893[Medline] [Order article via Infotrieve]. 30. Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995;377:454-457[Medline] [Order article via Infotrieve]. 31. Hörlein AJ, Näär AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor corepressor. Nature. 1995;377:397-403[Medline] [Order article via Infotrieve]. 32. Sande S, Privalsky M. Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with, and modulate the activity of, nuclear hormone receptors. Mol Endocrinol. 1996;10:813-825[Abstract]. 33. Nagy L, Kao H-Y, Chakravarti D, et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell. 1997;89:373-380[Medline] [Order article via Infotrieve]. 34. Heinzel T, Lavinsky RM, Mullen TM, et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature. 1997;387:43-48[Medline] [Order article via Infotrieve].
35.
Rachez C, Suldan Z, Ward J, et al.
A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system.
Genes Dev.
1998;12:1787-1800
36.
Fondell JD, Ge H, Roeder R.
Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex.
Proc Natl Acad Sci U S A.
1996;93:8329-8333
37.
Huang ME, Ye YC, Chen SR, et al.
Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia.
Blood.
1988;72:567-572
38.
Castaigne S, Chomienne C, Daniel MT, et al.
All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results.
Blood.
1990;76:1704-1709
39.
Chen ZX, Xue YQ, Zhang R, et al.
A clinical and experimental study on all-trans retinoic acid treated acute promyelocytic leukemia patients.
Blood.
1991;78:1413-1419
40.
Frankel SR, Eardley A, Heller G, et al.
All-trans retinoic acid for acute promyelocytic leukemia: results of the New York study.
Ann Intern Med.
1994;120:278-286
41.
Grignani F, Fagioli M, Alcalay M, et al.
Acute promyelocytic leukemia: from genetics to treatment [review].
Blood.
1994;83:10-25
42.
Pandolfi PP, Grignani F, Alcalay M, et al.
Structure and origin of the acute promyelocytic leukemia myl/RAR 43. de The H, Lavau C, Marchio A, et al. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66:675-684[Medline] [Order article via Infotrieve]. 44. Kakizuka A, Miller WH Jr, Umesono K, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991;66:663-674[Medline] [Order article via Infotrieve]. 45. Kastner P, Perez A, Lutz Y, et al. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 1992;11:629-642[Medline] [Order article via Infotrieve].
46.
Early E, Moores M, Kakizuka A, et al.
Transgenic expression of PML-RAR 47. David G, Terris B, Marchio A, Lavau C, Dejean A. The acute promyelocytic leukemia PML-RAR alpha protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice. Oncogene. 1997;14:1547-1554[Medline] [Order article via Infotrieve].
48.
Grisolano J, Wesselschmidt R, Pelicci PG, Ley T.
Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR
49.
He L-Z, Tribioli C, Rivi R, et al.
Acute leukemia with promyelocytic features in PML/RAR |
Top
Abstract
Introduction
B.