Identification and molecular cloning of a soluble human granulocyte-macrophage colony-stimulating factor receptor.

Raines, Maribeth A.; Liu, Lide; Quan, Shirley G.; Joe, Victor; DiPersio, John F.; Golde, David W.

doi:10.1073/pnas.88.18.8203

Cited by 88 publications

(43 citation statements)

References 37 publications

(36 reference statements)

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“…Therefore, we applied the sensitive technique of RT-PCR for analysis of expression. Primers were chosen to detect mRNA independent of alternative splicing (49). As a control, we compared the relative expression of the housekeeping GAPDH gene.…”

Section: Resultsmentioning

confidence: 99%

PU.1 (Spi-1) and C/EBPα Regulate Expression of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Gene

Hohaus

Petrovick

Voso

et al. 1995

Molecular and Cellular Biology

263

171

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Growth factor receptors play an important role in hematopoiesis. In order to further understand the mechanisms directing the expression of these key regulators of hematopoiesis, we initiated a study investigating the transcription factors activating the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor ␣ gene. Here, we demonstrate that the human GM-CSF receptor ␣ promoter directs reporter gene activity in a tissue-specific fashion in myelomonocytic cells, which correlates with its expression pattern as analyzed by reverse transcription PCR. The GM-CSF receptor ␣ promoter contains an important functional site between positions ؊53 and ؊41 as identified by deletion analysis of reporter constructs. We show that the myeloid and B cell transcription factor PU.1 binds specifically to this site. Furthermore, we demonstrate that a CCAAT site located upstream of the PU.1 site between positions ؊70 and ؊54 is involved in positive-negative regulation of the GM-CSF receptor ␣ promoter activity. C/EBP␣ is the major CCAAT/ enhancer-binding protein (C/EBP) form binding to this site in nuclear extracts of U937 cells. Point mutations of either the PU.1 site or the C/EBP site that abolish the binding of the respective factors result in a significant decrease of GM-CSF receptor ␣ promoter activity in myelomonocytic cells only. Furthermore, we demonstrate that in myeloid and B cell extracts, PU.1 forms a novel, specific, more slowly migrating complex (PU-SF) when binding the GM-CSF receptor ␣ promoter PU.1 site. This is the first demonstration of a specific interaction with PU.1 on a myeloid PU.1 binding site. The novel complex is distinct from that described previously as binding to B cell enhancer sites and can be formed by addition of PU.1 to extracts from certain nonmyeloid cell types which do not express PU.1, including T cells and epithelial cells, but not from erythroid cells. Furthermore, we demonstrate that the PU-SF complex binds to PU.1 sites found on a number of myeloid promoters, and its formation requires an intact PU.1 site adjacent to a single-stranded region. Expression of PU.1 in nonmyeloid cells can activate the GM-CSF receptor ␣ promoter. Deletion of the amino-terminal region of PU.1 results in a failure to form the PU-SF complex and in a concomitant loss of transactivation, suggesting that formation of the PU-SF complex is of functional importance for the activity of the GM-CSF receptor ␣ promoter. Finally, we demonstrate that C/EBP␣ can also activate the GM-CSF receptor ␣ promoter in nonmyeloid cells. These results suggest that PU.1 and C/EBP␣ direct the cell-type-specific expression of GM-CSF receptor ␣, further establish the role of PU.1 as a key regulator of hematopoiesis, and point to C/EBP␣ as an additional important factor in this process.

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Section: Resultsmentioning

confidence: 99%

PU.1 (Spi-1) and C/EBPα Regulate Expression of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Gene

Hohaus

Petrovick

Voso

et al. 1995

Molecular and Cellular Biology

263

171

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“…Alternative splicing produces at least 5 isoforms, some being membrane-bound and others being soluble [55][56][57][58][59].…”

Section: Pre-mrna Splicing and Parmentioning

confidence: 99%

The Human Pseudoautosomal Region (PAR): Origin, Function and Future

Mangs¹,

Morris

2007

197

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Abstract:The pseudoautosomal regions (PAR1 and PAR2) of the human X and Y chromosomes pair and recombine during meiosis. Thus genes in this region are not inherited in a strictly sex-linked fashion. PAR1 is located at the terminal region of the short arms and PAR2 at the tips of the long arms of these chromosomes. To date, 24 genes have been assigned to the PAR1 region. Half of these have a known function. In contrast, so far only 4 genes have been discovered in the PAR2 region. Deletion of the PAR1 region results in failure of pairing and male sterility. The gene SHOX (short stature homeobox-containing) resides in PAR1. SHOX haploinsufficiency contributes to certain features in Turner syndrome as well as the characteristics of Leri-Weill dyschondrosteosis. Only two of the human PAR1 genes have mouse homologues. These do not, however, reside in the mouse PAR1 region but are autosomal. The PAR regions seem to be relics of differential additions, losses, rearrangements and degradation of the X and Y chromosome in different mammalian lineages. Marsupials have three homologues of human PAR1 genes in their autosomes, although, in contrast to mouse, do not have a PAR region at all. The disappearance of PAR from other species seems likely and this region will only be rescued by the addition of genes to both X and Y, as has occurred already in lemmings. The present review summarizes the current understanding of the evolution of PAR and provides up-to-date information about individual genes residing in this region. THE X AND Y CHROMOSOMESThe human sex chromosomes (X and Y) originate from an ancestral homologous chromosome pair, which during mammalian evolution lost homology due to progressive degradation of the Y chromosome [1]. The X-chromosome in placental mammals represents approximately 5% of the haploid genome and the gene content is almost completely conserved amongst species. To ensure dosage compensation, most genes on the X are subject to X inactivation in females. The Y chromosome is much smaller than the X, being only 2-3% of the haploid genome, and is largely composed of repeated sequences. Most genes on the Y have relatives on the X chromosome and these are not subject to X inactivation. The degeneration of the Y chromosome has been researched and reviewed extensively [2][3][4][5][6]. THE PSEUDOAUTOSOMAL REGIONSThe pseudoautosomal regions (PAR1 and PAR2) are short regions of homology between the mammalian X and Y chromosomes. The PAR behave like an autosome and recombine during meiosis. Thus genes in this region are inherited in an autosomal rather than a strictly sex-linked fashion.PAR1 comprises 2.6 Mb of the short-arm tips of both X and Y chromosomes in humans and other great apes [7,8] and is required for pairing of the X and Y chromosomes during male meiosis. All characterized genes within PAR1 escape X inactivation. X-Y pairing in the PAR is thought to serve a critical function in spermatogenesis, at least in humans and mouse [9][10][11]. PAR2 is located at the tips of the long arms and is a much shor...

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“…Two major nonexclusive mechanisms are responsible for the generation of soluble cytokine receptors: proteolytic cleavage of transmembrane receptors catalyzed mostly by metalloproteases [15][16][17][18][19] or de novo synthesis of alternatively spliced mRNAs encoding soluble receptor molecules lacking a transmembrane domain. [20][21][22][23][24][25][26][27][28] Soluble cytokine receptors appear to be potent regulators of cytokine activities. Interference with the binding of cytokines to their membrane receptors and, thus, inhibition of cytokine signaling has been demonstrated to occur in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Meißner

Blum

Schnare

et al. 2001

Blood

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The common gamma-chain (␥c) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble ␥c (s␥c) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the fulllength ␥c showed that shedding of the transmembrane receptor led to the release of s␥c. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence s␥c release. In vivo, superantigen-induced stimulation of T cells enhanced s␥c serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of s␥c. A physiological role of s␥c was indicated by its capacity to specifically inhibit cell growth induced by ␥c-dependent cytokines. Mutational analysis revealed that the Cterminus and the WSKWS motif are essential for the cytokine inhibitory effect of the s␥c and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane ␥c by excess s␥c is the most likely mechanism of cell growth inhibition. It was implied that naturally produced s␥c is a negative modulator of ␥c-dependent cytokines. IntroductionThe murine common gamma-chain (␥c) is a 64-kd type 1 transmembrane protein of the cytokine receptor family. 1 Although the ␥c alone is unable to bind to cytokines, it has been shown to be an essential component of the cell surface receptor complexes of IL-2, IL-4, IL-7, IL-9, and IL-15. 1 Interaction of the respective cytokines with the ␥c within the receptor complexes results in the activation of the Janus kinase JAK3, 2 which subsequently interacts with Pyk2, a member of focal adhesion tyrosine kinases, leading to the phosphorylation of this protein. 3 Recent studies have shown that the ␥c is critical for lymphoid development because genetic defects of either this molecule 4 or JAK3 5 in humans or targeted deletions of the ␥c 6,7 or JAK3 8-10 in mice severely impair the development of T and B cells, leading to severe combined immune deficiency syndromes (SCID). 11 Soluble cytokine receptors and growth factor receptors are present as immunomodulatory molecules in body fluids of humans and mice (reviewed in references 12 and 14). Two major nonexclusive mechanisms are responsible for the generation of soluble cytokine receptors: proteolytic cleavage of transmembrane receptors catalyzed mostly by metalloproteases [15][16][17][18][19] or de novo synthesis of alternatively spliced mRNAs encoding soluble receptor molecules lacking a transmembrane domain. [20][21][22][23][24][25][26][27][28] ...

show abstract

Identification and molecular cloning of a soluble human granulocyte-macrophage colony-stimulating factor receptor.

Cited by 88 publications

References 37 publications

PU.1 (Spi-1) and C/EBPα Regulate Expression of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Gene

PU.1 (Spi-1) and C/EBPα Regulate Expression of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Gene

The Human Pseudoautosomal Region (PAR): Origin, Function and Future

A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

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