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Previous Article | Next Article 
Molecular and Cellular Biology, January 2003, p. 186-194, Vol. 23, No. 1
0270-7306/03/$08.00+0 DOI: 10.1128/MCB.23.1.186-194.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Howard Hughes Medical Institute, Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115,1 Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 100212
Received 2 August 2002/ Returned for modification 12 September 2002/ Accepted 1 October 2002
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ABSTRACT |
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INTRODUCTION |
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Mll is a mammalian member of the trx-G, and loss-of-function studies indicate that it is required for midgestational development. An Mll-exon3lacZ homozygous disruption results in embryonic death at E10.5 with multiple patterning defects including abnormal ganglia, absence of the maxillary branch of the first branchial arch, and pooling of erythroid precursors in the coelomic cavity (35). This Mll knockout revealed that Mll is required for the maintenance rather than the initiation of Hox gene expression in early embryogenesis (34). Although Mll-null embryos demonstrated correct initiation of Hox gene expression, including Hoxa7 and Hoxc8, the subsequent maintenance of the expression of these Hox genes was lost. Together, these studies indicate that Mll is critical for the proper maintenance of Hox gene expression during development.
Translocations of human chromosome segment 11q23 disrupt the MLL gene, resulting in a common chromosome abnormality encountered in acute leukemia, which is found in 80% of infant leukemias and the majority of chemotherapy-related leukemias following treatment with topoisomerase II inhibitors (12, 30). The MLL gene is composed of 37 exons and encodes a 3,969-amino-acid (aa) nuclear protein with multiple distinct domains including an N terminus with three AT-hook motifs, a DNA methyltransferase homology domain (DNMT), four PHD fingers, a transactivation domain, and a highly conserved SET domain at the C terminus (11, 15, 31) (see Fig. 1A). MLL is fused with more than 20 different chromosomal partners on translocation, resulting in multiple unique MLL fusion proteins. The MLL breakpoints are tightly clustered in an 8.3-kb genomic region containing exons 8 to 14, and the derivative 11 chromosome [der(11)] encodes the MLL fusion protein, which possesses 
1,300 aa of N-terminal MLL (12). The C-terminal fusion partners of MLL are very diverse, ranging from putative transcription factors to cytoplasmic structural proteins. This has raised the question whether there is any common property conferred by the fusion proteins (2).
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2253-2727. Oligonucleotides that encode the Flag or Myc epitope were inserted into the unique BstEII site of MLL to generate C-terminally Flag- or Myc-tagged MLL, respectively. Flag-tagged truncated MLL constructs were generated by inserting a stop codon into a SalI or PflMI site. A PCR fragment encoding aa 2720 to 3969 was inserted into the pCMV-Myc vector (Clontech) to generate Myc-tagged C180. A stop codon was added at the BstEII site to generate Myc-C150F/S. Green fluorescent protein (GFP) was inserted in frame at the BstEII site of MLL. A PCR fragment encoding red fluorescent protein (RFP) was cloned into pCDNA3, and the resultant vector was used to generate the RFP-MLL-GFP construct. Truncation mutants with a deletion of FYRC and SET domains (F/S) were constructed by adding a stop codon after either the Flag epitope or GFP. A NotI site was created in wild-type (wt) MLL to generate DG
AA and DGVAAA MLL mutants. MLL Ab preparation. MLL fragments consisting of aa 5 to 955 and aa 2829 to 2883 were expressed as glutathione S-transferase GST fusions in Escherichia coli BL21/DE3. GST-MLL-fusion proteins were purified as previously described (13) and injected into rabbits (Covance). Abs were purified from immunized rabbit serum by using a HiTrap protein A column (Amersham Pharmacia Biotech) as specified by the manufacturer.
Transient-transfection, immunoblotting, in vitro transcription and translation, and immunoprecipitation assays. Human embryonic kidney 293T cells were transiently transfected with the indicated MLL-expressing constructs by using Fugene 6 (Roche Molecular Biochemicals) as specified by the manufacturer. Cells were solubilized in RIPA buffer 48 h after transfection. Immunoprecipitation and immunoblot assays were performed as described previously (6) using indicated anti-Flag (Sigma), anti-N-terminal (anti-NT), or anti-CT Ab.35S-labeled MLL polypeptides were generated by in vitro transcription and translation using the TNT-coupled reticulocyte lysate system (Promega). Immunoprecipitation assays of35S-labeled polypeptides using anti-Flag antibody were described previously (6).
Indirect immunofluorescence and confocal microscopy. Fluorescence-tagged MLL was expressed in 293T cells. Cells were fixed in phosphate-buffered saline with 3% paraformaldehyde, stained with YOPRO-3 (Molecular Probes), and detected by confocal microscopy.
Purification of Flag-C180 and N-terminal sequence analysis. An MLL construct carrying a Flag tag at the C terminus was transfected into 293T cells. Cellular extracts purified from 30 10-cm dishes were incubated with anti-Flag Ab-coated beads. Immunoprecipitates were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene difluoride (PVDF) membrane. Coomassie blue staining demonstrated one predominant band, which was excised and subjected to N-terminal Edman degradation analysis.
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RESULTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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500 kDa). However, an Ab to an N-terminal region (aa 5 to 955; anti-NT) recognized instead an 320-kDa fragment in cells expressing a full-length MLL construct (Fig. 1C). Reciprocally, an Ab to a C-terminal region (aa 2829 to 2883; anti-CT) also failed to detect full-length MLL but did identify an 180-kDa fragment (Fig. 1D). This suggested that MLL may undergo a posttranslational cleavage. To test this hypothesis, we tagged the N-terminal or C-terminal portion of MLL with a Flag epitope (Fig. 1B). An anti-Flag Ab detected the same 320- and 180-kDa fragments (Fig. 1E), as did the anti-NT (Fig. 1C) and anti-CT (Fig. 1D) Abs. This confirmed that full-length MLL is cleaved into N-terminal p320 (N320) and C-terminal p180 (C180) fragments. A series of internal deletion mutants were subsequently generated to localize the cleavage site. The Flag-tagged mutant (MLL2253-2727) was not cleaved and was detected as a 450-kDa protein by all three Abs (Fig. 1B to E). In total, these data indicate that MLL is cleaved and that the cleavage site(s) resides between aa 2253 and 2727. N320 and C180 fragments form a post-cleavage complex which displays a distinct subnuclear colocalization. Numerous studies have demonstrated a punctate subnuclear localization for MLL utilizing Abs raised against the N-terminal portion of the protein (4, 5, 24, 32). Since MLL is proteolytically processed to two distinct fragments, one critical issue is whether C180 demonstrates the same or a unique subcellular localization compared to N320. To address this, RFP was fused to the N terminus of MLL and GFP was introduced into the C terminus. When this doubly tagged protein was expressed, it was cleaved correctly into RFP-N320 and GFP-C180 fragments (Fig. 2D). Expression of this dually fluorescent MLL protein in 293T cells resulted in the colocalization of RFP-N320 and GFP-C180 in a punctate nuclear pattern, as determined by confocal microscopy (Fig. 2A). This observation raised the possibility of a physical association between N320 and C180 fragments prompting the creation of a dually tagged construct bearing a Flag-tagged N terminus and a Myc-tagged C-terminus (Fig. 2B). Myc-C180 was coimmunoprecipitated with Flag-N320 by using the anti-Flag Ab (Fig. 2B). A reciprocal immunoprecipitation using an anti-Myc Ab coprecipitated the Flag-N320 as well as C180 fragments (data not shown). To examine whether endogenous MLL protein was proteolytically cleaved and assembled, cellular extracts from HeLa and 293T cells were immunoprecipitated with anti-CT Ab and subjected to Western blot analysis using either anti-CT or anti-NT Abs. The endogenous MLL protein of both cells was also processed into N320 and C180 fragments with evidence through their coimmunoprecipitation of a post-cleavage complex (Fig. 2C).
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F/S, Fig. 6). This C-terminally truncated mutant, MLLF/S, was proteolytically processed to the expected N320 fragment and the predictably smaller C150F/S fragment (Fig. 6). The C150F/S fragment did not coprecipitate N320 (Fig. 6). This confirms the in vitro interaction between the FYRC-plus-SET region of C180 and N320. Of note, although the C150F/S fragment was of comparable abundance to wt C180, we observed a 10-fold reduction in N320 levels in cells with mutant C150F/S (Fig. 6). This suggests that the interaction between N320 and C180 protects N320 from degradation. To further demonstrate the effect of the N320-C180 interaction on N320 stability, we coexpressed a Flag-tagged N-terminal MLL with either Myc-tagged C180 or C150F/S in 293T cells (Fig. 7A). In the presence of C180, the N-terminal MLL was stabilized and detected at high abundance (Fig. 7B, lane 1) compared to the markedly diminished level detected when expressed with C150F/S (lane 2). To estimate the half-life of the N-terminal MLL fragment, cells expressing these constructs had their protein synthesis inhibited by cycloheximide. Levels of N-terminal MLL were determined over a serial time course by anti-Flag Western blot analyses. In the presence of C180, the estimated half-life of N-terminal MLL was longer than 8 h (Fig. 7C). In contrast, when C150F/S, which fails to interact, was expressed, the estimated half-life of N-terminal MLL was shortened to 4 h (Fig. 7D). This confirms that the processed MLL N-terminal fragment must interact with the C-terminal fragment to avoid degradation and confer stability. Thus, one rationale for a dynamic interaction between cleaved MLL fragments is to regulate the levels of the N-terminal fragment of MLL.
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F/S construct lacking the FYRC and SET domains was labeled with RFP at its N terminus and GFP at its C terminus (Fig. 8). Confocal microscopy of cells expressing this doubly fluorescent construct revealed that there was no detectable expression of the RFP-N320 fragment (Fig. 8, left upper panel). Thus, because of the low level of RFP-N320, we could not accurately assess whether N320, which possesses previously defined subnuclear localization sequences (32), was itself capable of correct localization in the absence of interaction with C180. In contrast, GFP-C150F/S was easily detected in the nucleus but had lost its normal punctate subnuclear pattern and was now distributed diffusely throughout the nucleus (Fig. 8). This argues that the localization of C180 to the subnuclear compartment is governed by its association with N320, although we cannot exclude the possibility that localization is mediated directly through the FYRC and SET domains. Thus, the processing of MLL regulates both the abundance and the localization of MLL fragments, providing mechanisms to control target gene expression.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The precise mechanisms whereby MLL exerts its principal function to maintain the expression of target genes, including Hox genes, remain uncertain. However, the presence of conserved motifs with MLL provides some insight. MLL possesses domains with ascribed biochemical properties: the three AT hook motifs provide minor-groove DNA binding (31, 36), the DNMT homology domain binds methylated DNA differentially and can repress transcription (8, 11, 22, 36), a conserved subnuclear localization signal directs punctate nuclear distribution (32), the PHD fingers mediate protein-protein interaction (14), the transactivation domain interacts with CREB-binding protein (13), and the highly conserved SET domain binds to histone H3, Sbf1, and ASH1, as well as itself (2, 9, 17, 25). Here we identify the D/GVDD and D/GADD motifs and assign a role for them in MLL processing as well as identifying roles for the FYRN and FYRC domains. The FYRN and the FYRC plus SET domains mediate the interaction between the N320 and C180 subunits of MLL. Of note, Drosophila TRX also possesses FYRN and FYRC motifs, suggesting that it may also form a complex of processed fragments. Two distant MLL family members, ALR and MLL3, are present in the human genome (23, 29) but lack the D/GVDD cleavage motifs. Interestingly, they have a varied organization of domains compared to MLL, possessing a PHD domain, a FYRN domain, a FYRC domain, and a SET domain all clustered within the C-terminal 450 aa of ALR and MLL3. This highly conserved architecture is also present in Caenorhabditis elegans and Drosophila ALR homologues (27). The interaction between the FYRN and the FYRC plus SET domains noted here for MLL raises a testable possibility that ALR and MLL3 may have clustered these domains to create a similar functional moiety. Perhaps one role for the cleavage of MLL is to physically juxtapose these previously separated domains.
Chromosomal translocations in human leukemia which disrupt MLL produce a chimeric protein in which the N-terminal portion of MLL is fused to 1 of more than 20 partners. These fusion partners do not have any recognizable motif in common, and they range widely from nuclear factors to cytoplasmic proteins and cell junction proteins. Gene expression profiles of human leukemias bearing an MLL translocation identified a pattern of upregulated genes. Among these genes were some of the well-recognized targets of wt MLL, including HOXA4, HOXA5, and HOXA9 (1, 33). This argues that the N-terminal 1,300-aa portion of MLL is sufficient to confer at least some target gene specificity to MLL fusion proteins. Mice expressing an MLL-AF9 fusion product progressed to acute myeloid leukemia, establishing the oncogenic potential of MLL chimeric proteins (7). In contrast, Mll-exon8Myc mice in which a small myc epitope tag was fused with MLL failed to develop leukemia, arguing that a truncated MLL fragment was not in itself sufficient to cause transformation. However, Mll-exon8LacZ mice in which MLL was fused with the ß-galactosidase protein did progress to acute leukemia (10). ß-Galactosidase has been extensively used in transgenic mouse models and plays no independent, demonstrated role in tumor formation. The compilation of these findings indicates that individual fusion partners play an indispensable role but that they need not be directly oncogenic. The observations here concerning protein instability may provide an explanation. The FYRN domain, required for interaction of the processed MLL fragments, is located downstream of the chromosomal breakpoint, indicating that MLL fusion proteins would lose interaction with the stabilizing C180 component. Consequently, one testable characteristic that might prove to be shared by all the partner proteins is the capacity to confer protein stability to the MLL N terminus.
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ACKNOWLEDGMENTS |
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We thank E. Smith for editorial assistance and B. Malynn for helpful discussions and suggestions.
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FOOTNOTES |
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