Functional analysis of PU.1 domains in monocyte‐specific gene regulation

Nishiyama, Chiharu; Nishiyama, Makoto; Ito, Toshifumi; Masaki, Shigehiro; Masuoka, Nobutaka; Yamane, Hisakazu; Kitamura, Toshio; Ogawa, Hideoki; Okumura, Ko

doi:10.1016/s0014-5793(04)00116-4

Cited by 30 publications

(26 citation statements)

References 35 publications

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“…In addition, overexpression of PU.1 in CD34 ϩ human myeloid progenitors promotes LC development (10,11). In recent analysis, we found that monocyte-specific gene expression and monocyte-like morphological change were induced by overproduction of PU.1 in mouse bone marrow-derived mast cell progenitors (12,20,21). In this study, overproduction of PU.1 caused several monocyte-like characteristics on both BMMC and PMC, suggesting that developed mast cells still have the capacity to exhibit monocyte-like features.…”

Section: Discussionmentioning

confidence: 98%

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Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1

Ito

Nishiyama²,

Nishiyama

et al. 2005

The Journal of Immunology

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PU.1 is a myeloid- and lymphoid-specific transcription factor that belongs to the Ets family. Recently, we found that overproduction of PU.1 in mouse bone marrow-derived hemopoietic progenitor cells induced monocyte-specific gene expression and caused their monocyte-like morphological change. In the present study, PU.1 was overproduced by using retrovirus expression system in differentiated bone marrow-derived mast cells. By overexpression of PU.1, cell surface expression of MHC class II, CD11b, CD11c, and F4/80 was induced, accompanied by reduced expression of c-kit, a mast cell-specific marker. Morphology of PU.1-transfected cells was altered toward monocyte-like one. PU.1-overproducing cells acquired T cell stimulatory ability and showed an increase in response to LPS stimulation, while response through FcεRI was markedly reduced by overproduction of PU.1. These results suggest that the differentiated mast cells still have potential to display monocytic features. When PU.1 was overproduced in a different type of mast cell, peritoneal mast cells, similar monocyte-like morphological change, and the expression of CD11b and F4/80 were induced. However, surface level of CD11c and MHC class II was not affected. These results indicate that the potential capacity to exhibit monocytic features is different between both the mast cells.

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Section: Discussionmentioning

confidence: 98%

“…Infection of BMMC and PMC was performed, according to a previously reported method (12,20). In brief, pMX-puro (mock vector) and pMXpuro-PU.1 (for the expression of wild-type PU.1) were transiently introduced into Plat-E with Fugene6 (Roche Diagnostics).…”

Section: Transfectionmentioning

confidence: 99%

Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1

Ito

Nishiyama²,

Nishiyama

et al. 2005

The Journal of Immunology

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“…bZIP proteins bind to DNA via a leucine zipper structure that is required for dimerization and an adjacent basic region that directly contacts DNA (Landschulz et al, 1988). ETS and bZIP factors are important for the regulation of cytokine genes such as IL-1␤ (Yang et al, 2000) and IL-6 (Akira et al, 1990;Nishiyama et al, 2004). Indeed, we identified an AT3-bound genomic fragment of the IL-6 gene and previously have found upregulation of IL-6 in SCA3 cells and human brains , indicating that IL-6 may represent another potential target gene of AT3.…”

Section: Discussionmentioning

confidence: 99%

Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation

Evert¹,

Araujo²,

et al. 2006

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Ataxin-3 (AT3), the disease protein in spinocerebellar ataxia type 3 (SCA3), has been associated with the ubiquitin-proteasome system and transcriptional regulation. Here we report that normal AT3 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase-2 (MMP-2) gene promoter and represses transcription by recruitment of the histone deacetylase 3 (HDAC3), the nuclear receptor corepressor (NCoR), and deacetylation of histones bound to the promoter. Both normal and expanded AT3 physiologically interacted with HDAC3 and NCoR in a SCA3 cell model and human pons tissue; however, normal AT3-containing protein complexes showed increased histone deacetylase activity, whereas expanded AT3-containing complexes had reduced deacetylase activity. Consistently, histone analyses revealed an increased acetylation of total histone H3 in expanded AT3-expressing cells and human SCA3 pons. Expanded AT3 lost the repressor function and displayed altered DNA/chromatin binding that was not associated with recruitment of HDAC3, NCoR, and deacetylation of the promoter, allowing aberrant MMP-2 transcription via the transcription factor GATA-2. For transcriptional repression normal AT3 cooperates with HDAC3 and requires its intact ubiquitin-interacting motifs (UIMs), whereas aberrant transcriptional activation by expanded AT3 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain. These findings demonstrate that normal AT3 binds target promoter regions and represses transcription of a GATA-2-dependent target gene via formation of histone-deacetylating repressor complexes requiring its UIM-associated function. Expanded AT3 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions.

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“…CTSS is highly expressed in professional APCs, including B cells, dendritic cells, and macrophages, and is intimately tied to MHC class II maturation and function in both human and mouse APCs (8,9,13). Interestingly, several recent reports show that PU.1 can induce the expression of MHC class II in B cells, mast cells, monocytes, and dendritic cells (31)(32)(33)(34). This up-regulation of MHC class II in monocytes requires the acidic, glutamine-rich, and DNA binding domain, but not the proline-, glutamine-, serine-, and threonine-rich domain of PU.1.…”

Section: Discussionmentioning

confidence: 99%

PU.1 Regulates Cathepsin S Expression in Professional APCs

Wang

Baron

Zhu

et al. 2006

The Journal of Immunology

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Cathepsin S (CTSS) is a cysteine protease that is constitutively expressed in APCs and mediates processing of MHC class II-associated invariant chain. CTSS and the Ets family transcription factor PU.1 are highly expressed in cells of both myeloid (macrophages and dendritic cells) and lymphoid (B lymphocytes) lineages. Therefore, we hypothesized that PU.1 participates in the transcriptional regulation of CTSS in these cells. In A549 cells (a human epithelial cell line that does not express either CTSS or PU.1), the expression of PU.1 enhances CTSS promoter activity ∼5- to 10-fold. In RAW cells (a murine macrophage-like cell line that constitutively expresses both CTSS and PU.1), the expression of a dominant-negative PU.1 protein and a short-interfering RNA PU.1 construct attenuates basal CTSS promoter activity, mRNA levels, and protein expression. EMSAs show binding of PU.1 to oligonucleotides derived from the CTSS promoter at two different Ets consensus binding elements. Mutation of these sites decreases the baseline CTSS activity in RAW cells that constitutively express PU.1. Chromatin immunoprecipitation experiments show binding of PU.1 with the CTSS promoter in this same region. Finally, the expression of PU.1, in concert with several members of the IFN regulatory factor family, enhances CTSS promoter activity beyond that achieved by PU.1 alone. These data indicate that PU.1 participates in the regulation of CTSS transcription in APCs. Thus, manipulation of PU.1 expression may directly alter the endosomal proteolytic environment in these cells.

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Functional analysis of PU.1 domains in monocyte‐specific gene regulation

Cited by 30 publications

References 35 publications

Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1

Mast Cells Acquire Monocyte-Specific Gene Expression and Monocyte-Like Morphology by Overproduction of PU.1

Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation

PU.1 Regulates Cathepsin S Expression in Professional APCs

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