Human Proteinase-3 Expression Is Regulated by PU.1 in Conjunction with a Cytidine-rich Element

Sturrock, Anne; Franklin, Kerry F.; Hoidal, John R.

doi:10.1074/jbc.271.50.32392

Cited by 57 publications

(46 citation statements)

References 74 publications

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“…This coordinate regulation might be accounted for by conserved PU.1-, C/EBP-, and c-Myb-binding sites within their promoters (4,7,8,23), as we found that these three transcription factors cooperatively activate the NE proximal enhancer (4,5). Recent genetic mapping studies indicate that the most 3Ј PR-3 exon is located 3 kb upstream of the first NE exon, placing the myeloid protease enhancer within the large PR-3 second intron, 1 kb downstream of the PR-3 promoter.…”

Section: Fig 4 Enhancer Segment C1 Binds Sp1 and Ets Factorsmentioning

confidence: 99%

An Enhancer Located between the Neutrophil Elastase and Proteinase 3 Promoters Is Activated by Sp1 and an Ets Factor

Nuchprayoon

Shang

Simkevich

et al. 1999

Journal of Biological Chemistry

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The adjacent neutrophil elastase, proteinase 3, and azurocidin genes encode serine proteases expressed specifically in immature myeloid cells. Subclones of a 17-kilobase (kb) murine neutrophil elastase genomic clone were assessed for their ability to stimulate the neutrophil elastase promoter in 32D cl3 myeloid cells. Region ؊9.3 to ؊7.3 kb stimulated transcription 7-fold, whereas other genomic segments were inactive. This enhancer is located in the second intron of the proteinase-3 gene and so may regulate more than one gene in the myeloid protease cluster. Deletional analysis of the enhancer identified several segments which activated the neutrophil elastase and thymidine kinase promoters 3-6-fold. The most active segment was a 220-base pair region centered at ؊8.6 kb, which activated transcription 31-fold. This segment contains an Sp1 consensus site, which bound Sp1, flanked by two Ets family consensus sequences, which bound PU.1, GABP, and an Ets factor present in myeloid cell extracts. Mutation of the Sp1-binding site reduced enhancer activity 8-fold in 32D cl3 cells, and mutation of either or both Ets-binding sites reduced activity 3-4-fold. Sp1 activated the distal enhancer 5-fold, GABP 3-fold, and the combination 8-fold in Schneider cells.To identify transcriptional events that determine myeloid cell determination, we have been investigating the regulation of the neutrophil elastase (NE) 1 gene. NE is a microbicidal serine protease present in the primary granules of granulocytes and monocytes (1). In bone marrow, NE mRNA is present mainly in promyelocytes (2), and transcriptional regulation plays a key role in its lineage-specific expression (3). We isolated a 17-kb genomic murine NE clone and found that, like the human NE gene, the murine gene contains five exons and initiates transcription 30 bp downstream from a TATAA homology (4). We demonstrated that the 5Ј-flanking region of the NE gene contains a 60-bp proximal enhancer, located just upstream of the TATAA homology, which is strongly active in 32D cl3 myeloid cells differentiating in response to granulocyte-colony-stimulating factor (G-CSF), but only weakly active in uninduced 32D cl3 cells or in fibroblasts (4). This proximal enhancer is activated cooperatively by C/EBP, c-Myb, CBF, and Ets family members such as PU.1 or GABP (4 -6). The NE gene is located just downstream of the proteinase-3 (PR-3) gene, which in turn is located just downstream of the azurocidin gene (7). These three serine protease genes are expressed specifically and coordinately in immature myeloid cells (7), and the promoter of each contains conserved binding sites for C/EBP, c-Myb, and PU.1 (7,8).To determine whether the murine NE gene contains additional regulatory regions, we assessed the activity of NE genomic subclones functionally after transient transfection into 32D cl3 cells. A 2-kb NE genomic region extending from Ϫ7.3 to Ϫ9.3 kb stimulated the NE promoter 7-fold, and stimulated the herpes TK promoter as well, whereas none of the other subclones, from Ϫ7.3 to ϩ7.5 kb...

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Section: Fig 4 Enhancer Segment C1 Binds Sp1 and Ets Factorsmentioning

confidence: 99%

An Enhancer Located between the Neutrophil Elastase and Proteinase 3 Promoters Is Activated by Sp1 and an Ets Factor

Nuchprayoon

Shang

Simkevich

et al. 1999

Journal of Biological Chemistry

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“…Its DNA binding sequence exists almost ubiquitously in the promoters of myeloid-specific genes and has been shown to be functional in the promoters of Mpo, Ctsg, Ela2, Prtn3, Lyzs and Gcsfr. 19,[66][67][68][69][70][71] As well, C/EBP␣, Myb, Sp1, and Oct-1 are known to be involved in normal myeloid differentiation. 72 However, the microarray analysis showed that AML1-MTG8 did not enhance the expression of these genes in L-G cells (data not shown), and moreover, a recent report 73 showed that AML1-MTG8 down-regulates C/EBP␣ in t(8;21) AML.…”

Section: Figurementioning

confidence: 99%

Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia revealed by microarray analysis

2002

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“…The collection includes the high-affinity FcI/CD64 [73,74] and low-affinity FcIIIA/CD16 receptors [75]; the receptors for G-CSF [76], GM-CSF [77], and the colony-stimulating factor (CSF/cfms) [78]; proteinase-3 [79]; the adhesion molecules CD11b [80] and CD18 [81,82]; the scavenger receptor A gene [83] and the tyrosine kinase c-fes/c-fps [84,85]. For the B cell lineage, the promoter region of the J chain gene has been shown be PU.1-dependent [12].…”

Section: Promotersmentioning

confidence: 99%

Role of PU.1 in Hematopoiesis

1998

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The ETS-family transcription factor PU.1 is expressed in hematopoietic tissues, with significant levels of expression in the monocytic and B lymphocytic lineages. PU.1 is identical to the Spi-1 proto-oncogene which is associated with the generation of spleen focusforming virus-induced erythroleukemias. An extensive body of in vitro gene regulatory studies has implicated PU.1 as an important, versatile regulator of B lymphoid-and myeloid-specific genes. The first half of the review is designed to coalesce data generated from studies examining the two PU.1 "knockout" animals, which have prompted a reevaluation of the proposed function of PU.1 during hematopoiesis. During hematopoiesis, PU.1 is required for development along the lymphoid and myeloid lineages but needs to be downregulated during erythropoiesis. These unique functional characteristics of PU.1 will be exemplified by contrasting the function of PU.1 with other transcription factors required during fetal hematopoiesis. The second half of this review will reexamine the functional characteristics of PU.1 deduced from traditional biochemical and transactivation assays in light of recent experiments examining the functional behavior of PU.1 in an embryonic stem cell in vitro differentiation system. Working models of how PU.1 regulates promoter and enhancer regions in the B cell and myeloid lineage will be presented and discussed.

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Human Proteinase-3 Expression Is Regulated by PU.1 in Conjunction with a Cytidine-rich Element

Cited by 57 publications

References 74 publications

An Enhancer Located between the Neutrophil Elastase and Proteinase 3 Promoters Is Activated by Sp1 and an Ets Factor

An Enhancer Located between the Neutrophil Elastase and Proteinase 3 Promoters Is Activated by Sp1 and an Ets Factor

Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia revealed by microarray analysis

Role of PU.1 in Hematopoiesis

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