Structure and transcription of the mouse erythropoietin receptor gene.

Youssoufian, Hagop; Zon, Leonard I.; Orkin, Stuart H.; D’Andrea, Alan D.; Lodish, Harvey F.

doi:10.1128/mcb.10.7.3675

Cited by 118 publications

(88 citation statements)

References 40 publications

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“…The Ap-1 and GATA motifs should potentially be capable of initiating enhancer transcription in both the sense and antisense directions, since Ap-1 binding sites show dyad symmetry (32) and the GATA motif has been found in either orientation in the promoter of many erythroid genes (16,30,36,38,57). Indeed, both strands of the HS2 enhancer were transcribed; gene-tropic enhancer RNAs, however, appeared to be preferentially synthesized or stabilized (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transcription of the HS2 Enhancer toward a cis-Linked Gene Is Independent of the Orientation, Position, and Distance of the Enhancer Relative to the Gene

Kong

Bohl

et al. 1997

Molecular and Cellular Biology

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The locus control region (LCR) of the human ␤-globin gene domain is defined by four erythroid-cell-specific DNase I-hypersensitive (HS) sites, HS1, -2, -3, and -4, located 50 to 70 kb upstream of the ␤-globin gene in a transcriptional direction: 5Ј HS4-HS3-HS2-HS1-//-ε-G ␥-A ␥-␦-␤ 3Ј (17,20,37,50). The LCR has been shown by studies of natural deletions of ␥␦␤-thalassemia (8,11,24) and by gene transfer experiments (14,18,20,51) to be indispensable for erythroid-cell-specific and high-level transcription of cis-linked globin genes and transgenes. The mechanism by which the LCR regulates transcription of the distant embryonic ε-, fetal ␥-, and adult ␤-globin genes at the respective developmental stages is not fully understood.In previous studies examining the mechanism of LCR function, a number of laboratories have investigated the ability of the individual HS sites to activate the transcription of cislinked genes in cell lines and transgenic mice. Among the LCR HS sites, HS2 has been found to possess developmental-stageindependent enhancer function (52). It is capable of stimulating the transcription of embryonic ε-, fetal ␥-, and adult ␤-globin genes in erythroid cells at the corresponding developmental stages (9,28,34,42,45,47) and may therefore constitute a major functional component of the LCR. However, a recent targeted deletion study shows that deletion of the HS2 enhancer from the murine LCR generated only mild effects on the expression of the ␤-like globin genes (15), suggesting that HS2 is not essential for LCR function and that LCR function may be due to the contribution of the other HS sites. Surprisingly, similar targeted deletion of HS3 also did not cause significant changes in the expression of the ␤-like globin genes (22). These findings suggest that LCR function is due not to the contribution of any specific HS site but to a series of interactions among its functional components, including the enhancer elements underlying the HS sites.In the above-described targeted deletion studies, deleting the HS2 or the HS3 sequence from the endogenous murine LCR and inserting in its place an independent transcription unit-a neomycin-resistant gene driven by a strong promoter-has been found to disrupt LCR function and cause severe anemia in and the deaths of homozygous transgenic mice (15,21). In the human ␤-LCR, inserting an independent transcription unit at a location between the HS2 enhancer and the downstream globin genes also disrupted LCR function (23) and caused the distantly downstream ␤-globin gene to be transcriptionally turned off. The mechanism by which the transcription of a foreign gene within the LCR might disrupt LCR function is not clearly understood (21).In an attempt to delineate the functional mechanism of the HS2 enhancer and ultimately of the LCR, we have previously analyzed the transcriptional status of the HS2 enhancer in transfected recombinant chloramphenicol acetyltransferase (CAT) plasmids (53). This earlier study showed that the transfected HS2 enhancer is itself transcribed in eryt...

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Section: Discussionmentioning

confidence: 99%

Transcription of the HS2 Enhancer toward a cis-Linked Gene Is Independent of the Orientation, Position, and Distance of the Enhancer Relative to the Gene

Kong

Bohl

et al. 1997

Molecular and Cellular Biology

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“…The classical EPOR in hematopoietic cells is a cytokine type I receptor characterized by an extracellular N-terminal domain with conserved cysteines and a WSXWS-motif, a single hydrophobic transmembrane segment, and a cytosolic domain with no intrinsic kinase activity. 29 Homodimerization of the two transmembrane EPOR molecules binds one EPO molecule and leads to a conformational change, which in turn activates EPOR associated Janus family tyrosine kinase 2 (JAK2) molecules. Once activated, JAK2 phosphorylates distal parts of the receptors, which subsequently serve as docking sites for downstream signaling molecules.…”

Section: Epo Signaling In the Nervous Systemmentioning

confidence: 99%

“…Multiple signal transduction pathways are activated downstream of EPOR/JAK2. 8,29 In neurons these include signal transducers and activators of transcription (Stat), phosphatidylinositol 3-kinase (PI3K)/Akt, Ras/extracellular signal regulated kinase (ERK1/2), nuclear factor-kappa-B (NF-B), and calcium. 6,7,30,31 Brines and Cerami 7 have proposed that the cytoprotective effects of EPO and its nonhematopoietic derivative, the carbamoylated EPO (CEPO) are mediated by a heteromeric receptor complex comprised of one EPOR subunit and a dimer of the common beta-chain shared by the members of the interleukin-3 receptor family.…”

Section: Epo Signaling In the Nervous Systemmentioning

confidence: 99%

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

et al. 2009

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Summary:The growth factor erythropoietin (EPO) and erythropoietin receptors (EPOR) are expressed in the nervous system. Neuronal expression of EPO and EPOR peaks during brain development and is upregulated in the adult brain after injury. Peripherally administered EPO, and at least some of its variants, cross the blood-brain barrier, stimulate neurogenesis, neuronal differentiation, and activate brain neurotrophic, antiapoptotic, anti-oxidant and anti-inflammatory signaling. These mechanisms underlie their tissue protective effects in nervous system disorders. As the tissue protective functions of EPO can be separated from its stimulatory action on hematopoiesis, novel EPO derivatives and mimetics, such as asialo-EPO and carbamoylated EPO have been developed. While the therapeutic potential of the novel EPO derivatives continues to be characterized in preclinical studies, the experimental findings in support for the use of recombinant human (rh)EPO in human brain disease have already been translated to clinical studies in acute ischemic stroke, chronic schizophrenia, and chronic progressive multiple sclerosis. In this review article, we assess the studies on EPO and, in particular, on its structural or functional variants in experimental models of nervous system disorders, and we provide a short overview of the completed and ongoing clinical studies testing EPO as neuroprotective/neuroregenerative treatment option in neuropsychiatric disease.

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“…Recombinant human EPO (rHuEPO) has thus been adopted for the treatment of various types of anemia (Cheer and Wagstaff, 2004;Gassmann et al, 2003;Mittelman, 1996). EPO acts on its receptor (EPO-R) that belongs to the cytokine receptor superfamily (Youssoufian et al, 1993). Binding of EPO to the EPO-R initiates the activation of several signaling cascades, including JAK2/STAT5, MAPK and PI3K pathways .…”

Section: Introductionmentioning

confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

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Structure and transcription of the mouse erythropoietin receptor gene.

Cited by 118 publications

References 40 publications

Transcription of the HS2 Enhancer toward a cis-Linked Gene Is Independent of the Orientation, Position, and Distance of the Enhancer Relative to the Gene

Transcription of the HS2 Enhancer toward a cis-Linked Gene Is Independent of the Orientation, Position, and Distance of the Enhancer Relative to the Gene

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

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