- Open Access
MOZ-TIF2 repression of nuclear receptor-mediated transcription requires multiple domains in MOZ and in the CID domain of TIF2
© Yin et al; licensee BioMed Central Ltd. 2007
- Received: 05 May 2007
- Accepted: 13 August 2007
- Published: 13 August 2007
Fusion of the MOZ and TIF2 genes by an inv (8) (p11q13) translocation has been identified in patients with acute mixed-lineage leukemia. Characterization of the molecular structure of the MOZ-TIF2 fusion protein suggested that the fusion protein would effect on nuclear receptor signaling.
A series of deletions from the N-terminus of the MOZ-TIF2 fusion protein demonstrated that the MOZ portion is essential for nuclear localization of the fusion protein. Transient expression of MOZ-TIF2 dramatically decreased both basal and estradiol inducible reporter gene activity in an estrogen receptor element (ERE) driven luciferase reporter system and decreased androgen-inducible reporter gene activity in an androgen receptor element (ARE) luciferase reporter system. Deletions in the MOZ portion of the MOZ-TIF2 fusion protein reduced the suppression in the ER reporter system. Stable expression of MOZ-TIF2 inhibited retinoic acid (RA) inducible endogenous CD11b and C/EBPβ gene response. The suppression of the reporter systems was released with either a CID domain deletion or with mutations of leucine-rich repeats in the TIF2 portion of MOZ-TIF2. The co-expression of TIF2, but not CBP, with MOZ-TIF2 partially restored the inhibition of the reporter systems. In addition, analysis of protein interactions demonstrated MOZ-TIF2 interaction with the C-terminus of CBP through both the MOZ and TIF2 portions of the fusion protein.
MOZ-TIF2 inhibited nuclear receptor-mediated gene response by aberrant recruitment of CBP and both the MOZ and TIF2 portions are required for this inhibition.
- Retinoid Acid
- U937 Cell
- Acute Myelogenous Leukemia
- Nuclear Receptor Signaling
- Estrogen Receptor Binding Element
Chromosomal translocations resulting in MOZ-(monocytic leukemia zinc finger protein)-TIF2 (transcriptional intermediary factor 2) fusions occur in acute myelogenous leukemia and most commonly have been seen with AML of the French-American-British phenotype of M4/M5 subtype. The MOZ-TIF2 fusion protein consists of the N-terminus of MOZ and the C-terminus of TIF2. Patients with these translocations often exhibit rapid progression and poor response to therapy. Various translocations involving MOZ have been described such as MOZ-CBP (cAMP-response element binding protein t(8;16)(p11;p13), MOZ-P300 t(8;22)(p11;q13), and MOZ-TIF2 (inv(8)(p11q13). In a pediatric patient with therapy-related myelodysplastic syndrome a MOZ translocation was found between t(2;8)(p23;p11) [1–8]. In addition, a MOZ homologous protein, MORF (monocytic leukemia zinc finger protein-related factor) has been found fused to CBP via t(10;16)(q22;p13) in patients with AML and therapy-related myelodysplastic syndromes [9–11].
MOZ is a histone acetyltransferase (HAT) [12, 13] and plays a role in maintenance of hematopoietic stem cells [14, 15]. MOZ also functions as a transcription regulator to activate RUNX1 and RUNX2-mediated transcription through protein-protein interactions. Co-expression of RUNX1 and MOZ can synergistically activate the MIP-1 alpha promoter through a proximal RUNX binding site [16, 17]. The N- and C-termini of MOZ have different functions with the N-terminus responsible for transcription repression and the C-terminus for transcription activation. The MOZ-CBP fusion blocks RUNX1-mediated transcription. We have previously identified by yeast two-hybrid analysis and co-immunoprecipitation two human chromatin assembly factors, the p150 subunit of chromatin assembly factor (CAF) and anti-silencing function 1b (ASF1b), that interact with MOZ and the MOZ portion of the MOZ-TIF2 protein . In zebrafish, MOZ through its crucial histone acetyltransferase activity regulated Hox expression. A MOZ mutation caused a late defect in facial motor-neuron migration and led to a abnormality in pharyngeal arch developmental .
TIF2 belongs to the p160 protein family which also includes SRC-1 (Steroid receptor coactivator), TIF2/GRIP1/SRC-2, and pCIP/ACTR/AIB-1/RAC-3/TRAM-1/SRC-3. The functions of the p160 family have been well reviewed [20–24]. The molecular structure of TIF2 demonstrates several functional domains including a PAS/bHLH domain, a receptor interaction region, and two activation domains (AD) [25–28]. In nuclear receptor signaling, TIF2 binds to nuclear receptors predominately through its nuclear receptor interacting domain (NID) [29, 30] and recruits the transcriptional co-activators CBP/p300 through CBP interaction domain (CID/AD1) [27, 31] and CARM-1, an arginine methytransferase, through AD2 [32–35]. As a consequence, acetylation and methylation in histone H3 and the KIX domain of CBP/p300 activates the promoter and facilitates the basal transcriptional machinery. TIF2 knock-out mice displayed significantly reduced fertility and abnormalities in white adipose tissue and energy metabolism [36–38].
The expression of MOZ-TIF2 in a mouse model resulted in acute myelogenous leukemia (AML) and blocked the differentiation of stem cells to hematopoietic progenitors [39, 40]. The deletion of the CID in the TIF2 partner of MOZ-TIF2 abolished the leukemogenesis and blocked the inhibition by MOZ-TIF2 of RAR, PPAR, and p53-mediated transcription . MOZ-TIF2 also altered cofactor recruitment and histone modification at the RARbeta2 promoter . In this study, we demonstrate that the MOZ portion of the MOZ-TIF2 fusion protein is essential for nuclear localization of MOZ-TIF2 and describe MOZ-TIF2 repression of transcriptional activation by ER and AR. This inhibition depended not only on the CID domain in TIF2 portion but also on multiple domains in the MOZ portion. The forced expression of TIF2, but not CBP, could reverse the inhibition. Stable expression of MOZ-TIF2 altered the retinoid acid (RA)-mediated endogenous gene responses.
The structure of MOZ-TIF2 and expression of the fusion gene
MOZ-TIF2 affects the transcription activation of ER and AR
The leucine-rich repeats in the CID of TIF2 determines the inhibition in transcription activation of ER and AR by MOZ-TIF2
We next mutated the two leucine-rich repeats PDDLL and LLDQL in the CID domain of MOZ-TIF2 by mutating several leucines to alanines in the region between amino acids 1231 and 1270 (Figure 4C). The LLDQL repeat has previously been demonstrated to be a CBP binding motif  The mutation of two repeats significantly stimulated both estrogen (Figure 4A) and androgen (Figure 4B), activated transcription compared to wild type MOZ-TIF2. With the mutated MOZ-TIF2, ligand-stimulated transcription increased approximately 4.2 fold for ER and 8.9 fold for AR, respectively.
MOZ-TIF2-mediated repression of transcription can be partially restored by TIF2 but not CBP
MOZ-TIF2 interacts with CBP in the ER-mediated transcription complex
The MOZ portion of MOZ-TIF2 contributes to CBP binding and nuclear receptor-mediated transcription inhibition
MOZ-TIF2 inhibits expression of endogenous RA response genes in U937 cells
Previously, MOZ-TIF2 has been shown using reporter systems to repress both RA and PPAR gamma receptor mediated transcription in U937 cells and p53 mediated transcription in p53 null cell lines . In the investigations reported here, we used ER- and AR-mediated transcription reporter systems as models to study the effect of MOZ-TIF2 on nuclear receptor signaling in CV-1 and HEK293 cells, lines that have been widely used for the investigation of nuclear receptor signaling. We found that the MOZ-TIF2 fusion inhibited both ER and AR-mediated transcription compared both to the pcDNA3 vector alone and to MOZ and TIF2. The transcription inhibition by MOZ-TIF2 in ER mediated transcription occurred in both basal and estradiol-stimulation conditions. In the AR-mediated transcription system, MOZ-TIF2 exerted a strong suppression only of DHT induced transcription. The differences in the effect of MOZ-TIF2 on basal transcription in the ER and AR reporter systems may result either from MOZ-TIF2 exerting a ligand independent effect on the ERE binding element or promoter specific effects similar to those reported for other hormone receptors . We also observed that in the AR-mediated transcription system TIF2 decreased the response to DHT though to a far lesser extent than MOZ-TIF2. The effect of TIF2 again suggests promoter specific effects which may be related to the previously described interactions between LXXLL motifs of TIF2 with the ligand-binding domain of the androgen receptor that allowed for negative regulation . Some support for this explanation comes from the observation that TIF2 inhibits DHT stimulation of the PSA promoters though to a lesser degree than MOZ-TIF2. In addition, we demonstrated that expression of MOZ-TIF2 in U937 cells at levels similar to that of patient's leukemic blasts inhibited the response of endogenous genes, C/EBPβ and CD11b to RA, suggesting that MOZ-TIF2 could decrease nuclear receptor-mediated transcription in vivo.
To explore the universal inhibition of MOZ-TIF2 in nuclear receptor-mediated transcription, we tested the effect of MOZ-TIF2 on ER mediated transcription in K562 and HEK 293 cells. Interestingly, the inhibition by MOZ-TIF2 of basal and ligand-dependent transcription in an ER reporter system was not as great as observed in CV-1 cells, indicating that the repression by MOZ-TIF2 of nuclear receptor-mediated transcription may be cell-dependent. Cell specific effects are supported by the observation that MOZ-TIF2 repressed a p53-responsive reporter plasmid in CV-1 and HEK293 cells to a far lesser extent (data not shown) than has been reported in SaOs2 cells .
The MYST domain in MOZ has HAT activity and the domain is retained in the MOZ-TIF2 fusion. In our systems, a mutation in the acetyl-CoA binding site (G657D) of the MYST domain, which is known to abolish HAT activity , did not abrogate MOZ-TIF2-mediated repression of ER-mediated transcription and had only a slight effect on AR-mediated transcription (data not shown). These results imply that HAT activity of the MOZ portion has no functional significance in nuclear receptor mediated transcription by MOZ-TIF2 fusion protein. The non-essential role of HAT activity in the MOZ fusion protein has been observed previously as the abolishment of HAT activity in the MOZ-CBP fusion protein did not significantly change AML1-mediated transcription activity and the same mutation in MOZ-TIF2 was not required for transformation of myeloid cells while C2HC nucleosome recognition motif was essential for MOZ-TIF2 transformation [17, 40].
In nuclear receptor-mediated transcription, protein acetylation may be provided by recruitment of the coactivators, CBP/p300 via the p160 SRC family [48, 49]. CBP/p300 are universal transcription coactivators with HAT activity [50, 51] that participate in multiple transcriptional events mediated by viral oncoproteins, hematopoiesis-related transcription factors, tumor suppressors, and nuclear receptors through the regulation of histone acetylation and interaction with the basal transcriptional machinery [52–55]. CBP/p300 also contributes to the acetylation of non-histone proteins, such as Rb, E2F, and P53 and regulates cell growth and differentiation. Both deficient CBP/p300 and mutated CBP/p300 are relevant to the hematopoietic malignancies and solid tumors [56–59]. In the MOZ-TIF2 fusion, CID, a CBP interacting domain in TIF2 portion, is retained and this domain is required for inhibition of RA and PPRAγ receptor-mediated transcription and for leukemogenesis . We demonstrated that the deletion of this domain in MOZ-TIF2 removed the repression of ER and AR-mediated transcription and partially reversed the response of endogenous CD11b to RA. Furthermore, the mutations in two leucine-rich repeats of the CID showed a similar effect as the deletion. In contrast, the deletion of CID from TIF2 suppressed the ER and AR-mediated transcription suggesting that the binding of MOZ-TIF2 to CBP/p300 played a direct role in inhibition of ER and AR-mediated transcription by MOZ-TIF2. The expression level of CBP in cells has been reported as an important factor in the inhibition of p53-mediated transcription by MOZ-TIF2 . However, in the nuclear receptor-mediated transcription model increased expression of CBP did not alter the inhibition of ER-mediated transcription by MOZ-TIF2. In contrast, co-expressed wild type TIF2 interfered with MOZ-TIF2 inhibition suggesting that TIF2 may be an important competitor and cellular levels of TIF2 could modify inhibition of nuclear receptor mediated transcription.
By co-immunoprecipitation we demonstrated that ER, CBP, and MOZ-TIF2 were in same protein complex. It is known that in nuclear receptor-mediated transcription TIF2 recruits CBP/P300 via CID . Therefore, the interaction between CBP and MOZ-TIF2 could be explained by the binding of the CID moiety in the TIF2 portion of the fusion protein. However, we found that CBP was also co-precipitated by wild type MOZ, which suggested that the MOZ portion of MOZ-TIF2 could interact with CBP directly. In support of the participation of MOZ, the physical interaction between the MOZ portion (amino acids 1–759) of MOZ-TIF2 and the C-terminal of CBP (amino acids 1680 to 2441) was shown in GST pull-down experiments. The mapping of the CBP binding region in the MOZ N-terminus suggests multiple CBP binding sites. Analysis of the MOZ protein sequence shows a CBP binding sequence, FX(D/E)XXXL, is located in the MYST domain at amino acids 600–606. In addition, four binding consensus-like motifs, XX (D/E) XXXL, are in the PHD domain of MOZ (amino acids 1–253) and three XX (D/E) XXXL motifs are located in the MYST domain. It has been shown that any single substitution in FX (D/E) XXXL was not able to block the binding of E1A to CBP . The MOZ portion binding sites in CBP were in the CH3 domain which contains a transcriptional adapter motif (TRAM) (amino acids 1811–1822) which binds competitively to p53, E1A, E2F, and overlaps with the binding sites for mdm2, myoD, and P/CAF. The analysis of solution structure supports the binding ability of this domain . However, our results suggest that there is/are some CBP binding site(s) even beyond the PHD and MYST domains because a MOZ-TIF2 fragment with the deletion of both domains still bound to CBP. Interestingly, each CBP binding site in MOZ portion may be of similar importance in the suppression of nuclear hormone-stimulated transcription by MOZ-TIF2.
Co-activation of ER and AR by p160 SRC family members is through two sites of interaction. One interaction occurs between the NID of the p160 proteins and the AF2 domain of ER and AR. The other interaction occurs between the C-terminus of p160 proteins and the AF1 domain in N-terminus of ER and AR and within AR the later interaction is stronger than former [62–66]. In the MOZ-TIF2 protein, the NID of TIF2 has been eliminated by the chromosomal translocation. Loss of this domain will change the interaction of MOZ-TIF2 with ER and AR. In our study, although ER was co-immunoprecipated with MOZ-TIF2 the ER level was almost half that which was pulled down by wild type TIF2. It seems that MOZ-TIF2 may participate in the transcriptional complex of ER in a way different from wild type TIF2. There are two alternative ways for MOZ-TIF2 to interact with ER: MOZ-TIF2 could interact with the AF1 domain of ER or MOZ-TIF2 could interact through other complex members such as CBP which has been shown to bind directly to ER [67, 68].
Our work conclusively suggests that MOZ-TIF2 as a bidentate CBP binding protein competes with wild type TIF2 in ER and AR mediated transcription. The aberrant binding to ER or AR and CBP by MOZ-TIF2 disorders the complex for receptor signaling and may bring about abnormal acetylation of histone and non-histone proteins or cause other aberrant modifications, which finally lead to the inhibition of transcription activation by liganded ER and AR. In addition, the MOZ portion of the fusion protein not only determines the localization of MOZ-TIF2 within the cell but also contributes to the inhibition by MOZ-TIF2 of nuclear receptor activation.
The MOZ-TIF2 fusion cDNA was constructed by the joining of the PCR-created fusion fragments to the MOZ partner at a Hind3 site and the TIF2 partner at a Sac1 site in pBluescript KS phagemid vector. The fusion cDNA was subsequently subcloned into the pcDNA 3.1A (Invitrogen, Carlsbad, CA), pEGFP (BD Biosciences Clontech, Palo Alto CA), pGEX (Amersham Pharmacia Biotech, Piscataway, NJ), and pET-30 (Novagen, Madison WI). The luciferase reporter plasmid containing two ER binding elements plus a TK minimal promoter (Vit TKSL) was a kind gift from Dr. James Mathis. The luciferase reporter plasmid driven by the long promoter/enhancer (PL) carrying the sequence between -6480 and +12 nucleotides of PSA (prostate specific antigen) or driven by the core promoter (PS) from -648 to +12 nucleotides of PSA was a gift from Dr. Stephen P. Balk [69, 70].
RNA isolation and RT-PCR
The primer sets applied in PCR
CGT CGC TAC AGT GAG GGT GA
G TTT TCG CAA AAG AGA TAC TGG CT
CGT CGC TAC AGT GAG GGT GA
A GTG GAT TGG TTT GCG GCT C
GA GCA CCC GTT GGA CTT GGA
GA GGG CAC ACT GGC ATT TTC A
GAG GTT TTT GTC CGA GTG GTG G
TGG GTG GCA ATG GAA GAT GTA A
CA AAC GCA GGG AGC AGC AGT
T GTT TGG TTT CTG GTT GAG GGA
CA AAC GCA GGG AGC AGC AGT
T GTA TTC TTT TGG CAT TCG GGG
GG CAG CAA GGA GCG ATA GGA
G GGT TCC ATC TGC TTC TGT TTT G
CG GTG AGC CCC AAG AAG AAA
CCG AGA AGC ACT GTT ACC AAT CAT
GGA GCC CAG AAA ACA GCA CT
CCG AGA AGC ACT GTT ACC AAT CAT
GGA GCC CAG AAA ACA GCA CT
GC AAA AGA CGC CTG GTC TAT
CGT CGC TAC AGT GAG GGT GA
GC AAA AGA CGC CTG GTC TAT
CGT CGC TAC AGT GAG GGT GA
CCG AGA AGC ACT GTT ACC AAT CAT
C CAA GCA GCA GCA TCT AAC CAA C
G TCC CTG AAG ATG AAA GCC TCC T
AGT TGC CGA ATT GCA TCG A
GGC GTT CCC ACC AGA GAG A
CCT CGC AGG TCA AGA GCA A
ACA AGT TCC GCA GGG TGC T
Mutation and deletion
The primers used for the deletion and mutation
Cell culture and transfection
HEK293 and CV-1 cells were grown in DMEM (Mediatech Cellgro, Herndon VA) containing 10% fetal bovine serum (FBS). K562 AND U937 cells were grown in RPMI1640 with 10% FBS. Transfections of HEK293 and CV-1 cells were done with Lipofectamine Plus (Invitrogen, Carlsbad CA) and of K562 cells with FuGENE 6 transfection reagent (Roche Applied Science, Indianapolis IN). U937 cells were transfected by electroporation. Transiently transfected cells were harvested 24–48 hours after transfection as indicated for the specific studies. Stable transfected cells were selected with G418 for 2–3 weeks.
Subcellular location by fluorescent microscopy and immunofluorescence staining
To determine the subcellular location of MOZ-TIF2, a GFP fusion of MOZ-TIF2 was expressed in HEK293, K562, and CV1 cells by transient transfection. After 24 hours the cells were fixed in 1% paraformaldehyde and examined by epifluorescence microscopy. To examine localization of the MOZ-TIF2 protein and protein products of various MOZ-TIF mutations in living cells, cells were cultured in 6-well plates. After 24 hours of transfection, cells were stained with DRAQ5™ (AXXORA, LLC, San Diego, CA) and images collected on a laser scanning confocal microscope (Bio-Rad Laser Scanning System Radiance 2000/Nikon Eclipse TE300 microscope) with LaserSharp 2000 software (Bio-Rad, Hercules, CA). To observe co-localization between endogenous MOZ and CBP, HEK293 and Hela cells were fixed in 1% paraformaldehyde, blocked with 3% bovine serum albumin in PBS, and incubated with antibodies (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) against MOZ (N-19, sc-5713) at 1:100 and CBP (C-1, sc-7300) at 1:200. Nuclei were counterstained with TO-PRO®-3 iodide (In Vitrogen-Molecular Probes, Carisbad, CA) and images collected as above.
CV1 and HEK 293 cells were transfected by Lipofectamine Plus in 24-well plates with 350 to 400 ng of luciferase reporter plasmids, 100 ng of expression plasmids of MOZ, MOZ-TIF2, TIF2, MOZ-TIF2 mutants, and 50 ng of estrogen or androgen receptor expression vector. After 36 hours of induction with 50 nM of estradiol (E) or 5α-dihydrotestosterone (DHT) in medium containing 10% dextran-charcoal-stripped fetal calf serum, cells were lysed with Cell Culture Lysis Reagent (Promega, Madison WI) and the luciferase assay was performed in a Monolight® 2040 luciferase luminometer by adding 10 μl of cell lysate to 100 μl of reaction mix consisting of 1 × salt buffer with pH 7.8 (20 mM of Tricine, 1.07 mM (MgCO3)4Mg (OH)2· 5H2O, 2.67 mM MgSO4, 0.2 mM EDTA, 530 μM ATP, 33.3 μM DTT, 270 μM coenzyme A, and 470 μM potassium luciferin. The luciferase activity was standardized for transfection efficiency with β-galactosidase activity. All experiments were performed at least in quadruplicate and repeated at least twice.
Co-immunoprecipitation and immunoblotting
HEK293 cells were transfected either with EGFP or a His-tag fusion of MOZ, MOZ-TIF2, or TIF2. In some experiments, a vector expressing the human estrogen receptor was co-transfected. Cell lysates were prepared with individual homogenizers in lysis buffer (50 mM NaCl, 5 mM KCl, 1 mM EDTA, 20 mM HEPES, pH 7.6, 10% glycerol, and protease inhibitor cocktails (Roche Applied Science, Indianapolis IN)). Immunoprecipitation was conducted with antibodies against His-tag or EGFP. Briefly, 2 μg of agarose-conjugated anti-His-tag (Santa Cruz Biotechnology, Santa Cruz CA) or anti-GFP antibody (BD Biosciences, Palo Alto CA) bound to protein A/G-agarose (Santa Cruz Biotechnology, Santa Cruz CA) was added to about 500 μg protein of cell lysate, incubated at 4°C overnight with rotation, the precipitate collected by centrifugation and washed with phosphate buffered saline (PBS) containing 0.5 % NP-40. After the final wash, the pellet was separated by SDS-PAGE and the western analysis conducted with antibodies against CBP and estrogen receptor. In some experiments, RIPA buffer was used to extract whole cell protein for western analysis.
GST pull down assay
The GST fusion proteins were expressed with pGEX constructs containing designated cDNA fragments in BL21-CodonPlus®(DE3)-RIL cells (Stratagene, La Jolla CA). The expressed GST fusion protein was purified with the GST Purification Module (Amersham Pharmacia Biotech, England), fractionated by SDS-PAGE, and proteins detected by staining with Coomassie Blue. To perform the GST pull down affinity assay, [35S] Met-labeled proteins were produced with the Single Tube Protein® System 3 (Novagen, Madison WI) from pET 30 vectors containing designated cDNA fragments. The binding reaction was conducted with 5 μl of in vitro-translated protein and 3–5 μg of GST or GST fusion protein bound to Sepharose 4B beads in 200 μl binding buffer (50 Mm Tris-HCl, pH 8.0, 100 mM NaCl, 0.3 mM DTT, 10 mM MgCl2, 10% glycerol, 0.1% NP40). The reaction was performed at 4°C for 1 hour followed by five washes of the beads with binding buffer, separation of bound proteins by SDS PAGE followed by autoradiography. In some experiments, non-isotope labeled X-press-tagged proteins were used and proteins pulled down by GST-fusion were examined by anti X-press antibody (Invitrogen Co., Carisbad, CA).
We thank Mark A Dayton, PhD, MD, for his participation in the RT-PCR experiments and data analysis. This work was fully supported by Feist-Weiller Cancer Center, LSUHSC-Shreveport.
- Liang J, Prouty L, Williams BJ, Dayton MA, Blanchard KL: Acute mixed lineage leukemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2. Blood. 1998, 92 (6): 2118-2122.PubMedGoogle Scholar
- Borrow J, Stanton VP, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE: The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet. 1996, 14 (1): 33-41. 10.1038/ng0996-33View ArticlePubMedGoogle Scholar
- Panagopoulos I, Isaksson M, Lindvall C, Bjorkholm M, Ahlgren T, Fioretos T, Heim S, Mitelman F, Johansson B: RT-PCR analysis of the MOZ-CBP and CBP-MOZ chimeric transcripts in acute myeloid leukemias with t(8;16)(p11;p13). Genes Chromosomes Cancer. 2000, 28 (4): 415-424. 10.1002/1098-2264(200008)28:4<415::AID-GCC7>3.0.CO;2-IView ArticlePubMedGoogle Scholar
- Chaffanet M, Gressin L, Preudhomme C, Soenen-Cornu V, Birnbaum D, Pebusque MJ: MOZ is fused to p300 in an acute monocytic leukemia with t(8;22). Genes Chromosomes Cancer. 2000, 28 (2): 138-144. 10.1002/(SICI)1098-2264(200006)28:2<138::AID-GCC2>3.0.CO;2-2View ArticlePubMedGoogle Scholar
- Kitabayashi I, Aikawa Y, Yokoyama A, Hosoda F, Nagai M, Kakazu N, Abe T, Ohki M: Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. Leukemia. 2001, 15 (1): 89-94. 10.1038/sj.leu.2401983View ArticlePubMedGoogle Scholar
- Carapeti M, Aguiar RC, Goldman JM, Cross NC: A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood. 1998, 91 (9): 3127-3133.PubMedGoogle Scholar
- Carapeti M, Aguiar RC, Watmore AE, Goldman JM, Cross NC: Consistent fusion of MOZ and TIF2 in AML with inv(8)(p11q13). Cancer Genet Cytogenet. 1999, 113 (1): 70-72. 10.1016/S0165-4608(99)00007-2View ArticlePubMedGoogle Scholar
- Imamura T, Kakazu N, Hibi S, Morimoto A, Fukushima Y, Ijuin I, Hada S, Kitabayashi I, Abe T, Imashuku S: Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11). Genes Chromosomes Cancer. 2003, 36 (4): 413-419. 10.1002/gcc.10172View ArticlePubMedGoogle Scholar
- Panagopoulos I, Fioretos T, Isaksson M, Samuelsson U, Billstrom R, Strombeck B, Mitelman F, Johansson B: Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum Mol Genet. 2001, 10 (4): 395-404. 10.1093/hmg/10.4.395View ArticlePubMedGoogle Scholar
- Kojima K, Kaneda K, Yoshida C, Dansako H, Fujii N, Yano T, Shinagawa K, Yasukawa M, Fujita S, Tanimoto M: A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13). Br J Haematol. 2003, 120 (2): 271-273. 10.1046/j.1365-2141.2003.04059.xView ArticlePubMedGoogle Scholar
- Vizmanos JL, Larrayoz MJ, Lahortiga I, Floristan F, Alvarez C, Odero MD, Novo FJ, Calasanz MJ: t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia. Genes Chromosomes Cancer. 2003, 36 (4): 402-405. 10.1002/gcc.10174View ArticlePubMedGoogle Scholar
- Champagne N, Bertos NR, Pelletier N, Wang AH, Vezmar M, Yang Y, Heng HH, Yang XJ: Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. J Biol Chem. 1999, 274 (40): 28528-28536. 10.1074/jbc.274.40.28528View ArticlePubMedGoogle Scholar
- Yang XJ: The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 2004, 32 (3): 959-976. 10.1093/nar/gkh252PubMed CentralView ArticlePubMedGoogle Scholar
- Thomas T, Corcoran LM, Gugasyan R, Dixon MP, Brodnicki T, Nutt SL, Metcalf D, Voss AK: Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev. 2006, 20 (9): 1175-1186. 10.1101/gad.1382606PubMed CentralView ArticlePubMedGoogle Scholar
- Katsumoto T, Aikawa Y, Iwama A, Ueda S, Ichikawa H, Ochiya T, Kitabayashi I: MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev. 2006, 20 (10): 1321-1330. 10.1101/gad.1393106PubMed CentralView ArticlePubMedGoogle Scholar
- Bristow CA, Shore P: Transcriptional regulation of the human MIP-1alpha promoter by RUNX1 and MOZ. Nucleic Acids Res. 2003, 31 (11): 2735-2744. 10.1093/nar/gkg401PubMed CentralView ArticlePubMedGoogle Scholar
- Kitabayashi I, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M: Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. Embo J. 2001, 20 (24): 7184-7196. 10.1093/emboj/20.24.7184PubMed CentralView ArticlePubMedGoogle Scholar
- Yin H: MOZ-TIF2 Fusion May Affect Chromatin Assembly by Alteration of Interactions Between Histone Chaperone Proteins, CAF1 And ASF1, and MOZ and CBP. A Potential Role in Leukemogenesis. blood. 2003, 102: 572a-Google Scholar
- Miller CT, Maves L, Kimmel CB: moz regulates Hox expression and pharyngeal segmental identity in zebrafish. Development. 2004, 131 (10): 2443-2461. 10.1242/dev.01134View ArticlePubMedGoogle Scholar
- Leo C, Chen JD: The SRC family of nuclear receptor coactivators. Gene. 2000, 245 (1): 1-11. 10.1016/S0378-1119(00)00024-XView ArticlePubMedGoogle Scholar
- Xu J, Li Q: Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol Endocrinol. 2003, 17 (9): 1681-1692. 10.1210/me.2003-0116View ArticlePubMedGoogle Scholar
- Dilworth FJ, Chambon P: Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene. 2001, 20 (24): 3047-3054. 10.1038/sj.onc.1204329View ArticlePubMedGoogle Scholar
- McKenna NJ, O'Malley BW: Combinatorial control of gene expression by nuclear receptors and coregulators. Cell. 2002, 108 (4): 465-474. 10.1016/S0092-8674(02)00641-4View ArticlePubMedGoogle Scholar
- Rosenfeld MG, Glass CK: Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem. 2001, 276 (40): 36865-36868. 10.1074/jbc.R100041200View ArticlePubMedGoogle Scholar
- Hong H, Kohli K, Trivedi A, Johnson DL, Stallcup MR: GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci U S A. 1996, 93 (10): 4948-4952. 10.1073/pnas.93.10.4948PubMed CentralView ArticlePubMedGoogle Scholar
- Voegel JJ, Heine MJ, 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 (14): 3667-3675.PubMed CentralPubMedGoogle Scholar
- Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H: The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. Embo J. 1998, 17 (2): 507-519. 10.1093/emboj/17.2.507PubMed CentralView ArticlePubMedGoogle Scholar
- Chen SL, Dowhan DH, Hosking BM, Muscat GE: The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation. Genes Dev. 2000, 14 (10): 1209-1228.PubMed CentralPubMedGoogle Scholar
- Ding XF, Anderson CM, Ma H, Hong H, Uht RM, Kushner PJ, Stallcup MR: Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol. 1998, 12 (2): 302-313. 10.1210/me.12.2.302View ArticlePubMedGoogle Scholar
- Berrevoets CA, Doesburg P, Steketee K, Trapman J, Brinkmann AO: Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2). Mol Endocrinol. 1998, 12 (8): 1172-1183. 10.1210/me.12.8.1172View ArticlePubMedGoogle Scholar
- Ma H, Hong H, Huang SM, Irvine RA, Webb P, Kushner PJ, Coetzee GA, Stallcup MR: Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell Biol. 1999, 19 (9): 6164-6173.PubMed CentralPubMedGoogle Scholar
- Chen D, Huang SM, Stallcup MR: Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. J Biol Chem. 2000, 275 (52): 40810-40816. 10.1074/jbc.M005459200View ArticlePubMedGoogle Scholar
- Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR: Regulation of transcription by a protein methyltransferase. Science. 1999, 284 (5423): 2174-2177. 10.1126/science.284.5423.2174View ArticlePubMedGoogle Scholar
- Teyssier C, Chen D, Stallcup MR: Requirement for multiple domains of the protein arginine methyltransferase CARM1 in its transcriptional coactivator function. J Biol Chem. 2002, 277 (48): 46066-46072. 10.1074/jbc.M207623200View ArticlePubMedGoogle Scholar
- Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR: Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci U S A. 2005, 102 (10): 3611-3616. 10.1073/pnas.0407159102PubMed CentralView ArticlePubMedGoogle Scholar
- Gehin M, Mark M, Dennefeld C, Dierich A, Gronemeyer H, Chambon P: The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP. Mol Cell Biol. 2002, 22 (16): 5923-5937. 10.1128/MCB.22.16.5923-5937.2002PubMed CentralView ArticlePubMedGoogle Scholar
- Mark M, Yoshida-Komiya H, Gehin M, Liao L, Tsai MJ, O'Malley BW, Chambon P, Xu J: Partially redundant functions of SRC-1 and TIF2 in postnatal survival and male reproduction. Proc Natl Acad Sci U S A. 2004, 101 (13): 4453-4458. 10.1073/pnas.0400234101PubMed CentralView ArticlePubMedGoogle Scholar
- Picard F, Gehin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, Auwerx J: SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002, 111 (7): 931-941. 10.1016/S0092-8674(02)01169-8View ArticlePubMedGoogle Scholar
- Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N, Rowan R, Amaral S, Curley D, Williams IR, Akashi K, Gilliland DG: MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004, 6 (6): 587-596. 10.1016/j.ccr.2004.10.015View ArticlePubMedGoogle Scholar
- Deguchi K, Ayton PM, Carapeti M, Kutok JL, Snyder CS, Williams IR, Cross NC, Glass CK, Cleary ML, Gilliland DG: MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell. 2003, 3 (3): 259-271. 10.1016/S1535-6108(03)00051-5View ArticlePubMedGoogle Scholar
- Kindle KB, Troke PJ, Collins HM, Matsuda S, Bossi D, Bellodi C, Kalkhoven E, Salomoni P, Pelicci PG, Minucci S, Heery DM: MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function. Mol Cell Biol. 2005, 25 (3): 988-1002. 10.1128/MCB.25.3.988-1002.2005PubMed CentralView ArticlePubMedGoogle Scholar
- Collins HM, Kindle KB, Matsuda S, Ryan C, Troke PJ, Kalkhoven E, Heery DM: MOZ-TIF2 alters cofactor recruitment and histone modification at the RARbeta2 promoter: differential effects of MOZ fusion proteins on CBP- and MOZ-dependent activators. J Biol Chem. 2006, 281 (25): 17124-17133. 10.1074/jbc.M602633200View ArticlePubMedGoogle Scholar
- Yamamoto H, Kihara-Negishi F, Yamada T, Suzuki M, Nakano T, Oikawa T: Interaction between the hematopoietic Ets transcription factor Spi-B and the coactivator CREB-binding protein associated with negative cross-talk with c-Myb. Cell Growth Differ. 2002, 13 (2): 69-75.PubMedGoogle Scholar
- Goldman PS, Tran VK, Goodman RH: The multifunctional role of the co-activator CBP in transcriptional regulation. Recent Prog Horm Res. 1997, 52: 103-19; discussion 119-20.PubMedGoogle Scholar
- O'Connor MJ, Zimmermann H, Nielsen S, Bernard HU, Kouzarides T: Characterization of an E1A-CBP interaction defines a novel transcriptional adapter motif (TRAM) in CBP/p300. J Virol. 1999, 73 (5): 3574-3581.PubMed CentralPubMedGoogle Scholar
- Zhang H, Yi X, Sun X, Yin N, Shi B, Wu H, Wang D, Wu G, Shang Y: Differential gene regulation by the SRC family of coactivators. Genes Dev. 2004, 18 (14): 1753-1765. 10.1101/gad.1194704PubMed CentralView ArticlePubMedGoogle Scholar
- Wang Q, Lu J, Yong EL: Ligand- and coactivator-mediated transactivation function (AF2) of the androgen receptor ligand-binding domain is inhibited by the cognate hinge region. J Biol Chem. 2001, 276 (10): 7493-7499. 10.1074/jbc.M009916200View ArticlePubMedGoogle Scholar
- Kim MY, Hsiao SJ, Kraus WL: A role for coactivators and histone acetylation in estrogen receptor alpha-mediated transcription initiation. Embo J. 2001, 20 (21): 6084-6094. 10.1093/emboj/20.21.6084PubMed CentralView ArticlePubMedGoogle Scholar
- Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG: Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 2001, 276 (21): 18375-18383. 10.1074/jbc.M100800200View ArticlePubMedGoogle Scholar
- Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y: The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996, 87 (5): 953-959. 10.1016/S0092-8674(00)82001-2View ArticlePubMedGoogle Scholar
- Bannister AJ, Kouzarides T: The CBP co-activator is a histone acetyltransferase. Nature. 1996, 384 (6610): 641-643. 10.1038/384641a0View ArticlePubMedGoogle Scholar
- von Mikecz A, Zhang S, Montminy M, Tan EM, Hemmerich P: CREB-binding protein (CBP)/p300 and RNA polymerase II colocalize in transcriptionally active domains in the nucleus. J Cell Biol. 2000, 150 (1): 265-273. 10.1083/jcb.150.1.265PubMed CentralView ArticlePubMedGoogle Scholar
- Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y: A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature. 1996, 382 (6589): 319-324. 10.1038/382319a0View ArticlePubMedGoogle Scholar
- Vo N, Goodman RH: CREB-binding protein and p300 in transcriptional regulation. J Biol Chem. 2001, 276 (17): 13505-13508.View ArticlePubMedGoogle Scholar
- Avantaggiati ML, Ogryzko V, Gardner K, Giordano A, Levine AS, Kelly K: Recruitment of p300/CBP in p53-dependent signal pathways. Cell. 1997, 89 (7): 1175-1184. 10.1016/S0092-8674(00)80304-9View ArticlePubMedGoogle Scholar
- Iyer NG, Ozdag H, Caldas C: p300/CBP and cancer. Oncogene. 2004, 23 (24): 4225-4231. 10.1038/sj.onc.1207118View ArticlePubMedGoogle Scholar
- Goodman RH, Smolik S: CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000, 14 (13): 1553-1577.PubMedGoogle Scholar
- Rebel VI, Kung AL, Tanner EA, Yang H, Bronson RT, Livingston DM: Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci U S A. 2002, 99 (23): 14789-14794. 10.1073/pnas.232568499PubMed CentralView ArticlePubMedGoogle Scholar
- McInerney EM, Rose DW, Flynn SE, Westin S, Mullen TM, Krones A, Inostroza J, Torchia J, Nolte RT, Assa-Munt N, Milburn MV, Glass CK, Rosenfeld MG: Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev. 1998, 12 (21): 3357-3368.PubMed CentralView ArticlePubMedGoogle Scholar
- Sheppard HM, Harries JC, Hussain S, Bevan C, Heery DM: Analysis of the steroid receptor coactivator 1 (SRC1)-CREB binding protein interaction interface and its importance for the function of SRC1. Mol Cell Biol. 2001, 21 (1): 39-50. 10.1128/MCB.21.1.39-50.2001PubMed CentralView ArticlePubMedGoogle Scholar
- De Guzman RN, Liu HY, Martinez-Yamout M, Dyson HJ, Wright PE: Solution structure of the TAZ2 (CH3) domain of the transcriptional adaptor protein CBP. J Mol Biol. 2000, 303 (2): 243-253. 10.1006/jmbi.2000.4141View ArticlePubMedGoogle Scholar
- Alen P, Claessens F, Verhoeven G, Rombauts W, Peeters B: The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription. Mol Cell Biol. 1999, 19 (9): 6085-6097.PubMed CentralPubMedGoogle Scholar
- Bevan CL, Hoare S, Claessens F, Heery DM, Parker MG: The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol. 1999, 19 (12): 8383-8392.PubMed CentralPubMedGoogle Scholar
- He B, Minges JT, Lee LW, Wilson EM: The FXXLF motif mediates androgen receptor-specific interactions with coregulators. J Biol Chem. 2002, 277 (12): 10226-10235. 10.1074/jbc.M111975200View ArticlePubMedGoogle Scholar
- Benecke A, Chambon P, Gronemeyer H: Synergy between estrogen receptor alpha activation functions AF1 and AF2 mediated by transcription intermediary factor TIF2. EMBO Rep. 2000, 1 (2): 151-157. 10.1093/embo-reports/kvd028PubMed CentralView ArticlePubMedGoogle Scholar
- Webb P, Nguyen P, Shinsako J, Anderson C, Feng W, Nguyen MP, Chen D, Huang SM, Subramanian S, McKinerney E, Katzenellenbogen BS, Stallcup MR, Kushner PJ: Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol Endocrinol. 1998, 12 (10): 1605-1618. 10.1210/me.12.10.1605View ArticlePubMedGoogle Scholar
- Heery DM, Hoare S, Hussain S, Parker MG, Sheppard H: Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors. J Biol Chem. 2001, 276 (9): 6695-6702. 10.1074/jbc.M009404200View ArticlePubMedGoogle Scholar
- Heery DM, Kalkhoven E, Hoare S, Parker MG: A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997, 387 (6634): 733-736. 10.1038/42750View ArticlePubMedGoogle Scholar
- Cleutjens KB, van der Korput HA, van Eekelen CC, van Rooij HC, Faber PW, Trapman J: An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol Endocrinol. 1997, 11 (2): 148-161. 10.1210/me.11.2.148View ArticlePubMedGoogle Scholar
- Huang W, Shostak Y, Tarr P, Sawyers C, Carey M: Cooperative assembly of androgen receptor into a nucleoprotein complex that regulates the prostate-specific antigen enhancer. J Biol Chem. 1999, 274 (36): 25756-25768. 10.1074/jbc.274.36.25756View ArticlePubMedGoogle Scholar
- Dayton MA, Knobloch TJ: Multiple phosphotyrosine phosphatase mRNAs are expressed in the human lung fibroblast cell line WI-38. Recept Signal Transduct. 1997, 7 (4): 241-256.PubMedGoogle Scholar
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