CNS Lupus and the Blood-Brain Barrier

Hoffman, Steven A.; Harbeck, Ronald J.

doi:10.1007/978-1-4615-7255-8_13

Cited by 15 publications

(9 citation statements)

References 97 publications

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“…This signaling subunit is utilized by several cytokines including IL-6, IL-11, OSM, LIF, and CNTF (17). Interestingly, IL-6, IL-11, and LIF have effects on megakaryocytopoiesis (31)(32)(33). Perhaps the ability to activate STAT1 and STAT3 underlies the effects common to TPO and these other cytokines.…”

Section: Resultsmentioning

confidence: 99%

Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation.

Gurney¹,

Wong²,

Henzel³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

171

133

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ABSTRACTc-Mpl, a member of the hematopoietic cytokine receptor family, is the receptor for thrombopoietin. To investigate signal transduction by c-Mpl, a chimeric receptor, composed of the extracellular domain of human growth hormone receptor and the intracellular domain of c-Mpl, was introduced into the interleukin 3-dependent cell line Ba/F3. In response to growth hormone, this chimeric receptor induced growth in the absence ofinterleukin 3. Deletion analysis of the 123-amino acid intracellular domain indicated that the elements responsible for this effect are present within the 63 amino acids proximal to the transmembrane domain. Mutation of the recently described box 1 motif abrogated the proliferative response. Tyrosine phosphorylation of the tyrosine kinase JAK-2 and activation of STAT proteins were dependent on box 1 and sequences within 63 amino acids ofthe plasma membrane. STAT proteins activated by thrombopoietin in a megakaryocytic cell line were purified and shown to be STATi and STAT3. A separate region located at the C terminus of the c-Mpl intracellular domain was found to be required for induction of Shc phosphorylation and c-fos mRNA accumulation, suggesting involvement of the Ras signal transduction pathway. Thus, at least two distinct regions are involved in signal transduction by the c-Mpl.c-Mpl, a member of the cytokine receptor superfamily, was originally identified as the cellular homolog of a retroviral oncogene (1). The extracellular domain of c-Mpl contains two repeats of a characteristic domain structure that includes four conserved cysteine residues and a WSXWS motif at its C terminus. Overall, c-Mpl exhibits highest homology to the erythropoietin (Epo) and interleukin 3 (IL-3) receptors (2). c-Mpl expression appears largely limited to tissues that support hematopoiesis: bone marrow, spleen, and fetal liver (3). The receptor is highly expressed in CD34+ cells and cells of the megakaryocyte lineage, suggesting a role in the regulation of platelet production. Involvement in regulating megakaryocytopoiesis has recently been confirmed through the study of mice deficient in c-Mpl (4). These mice, generated by gene targeting, display pronounced thrombocytopenia with an 85% decrease in their numbers of platelets and megakaryocytes, but they have normal levels of other hematopoietic cell types.Recently, our laboratory and others have purified and cloned the ligand for c-Mpl and shown it to be thrombopoietin (TPO), an activity capable of stimulating the proliferation and maturation of megakaryocytes (reviewed in ref. 5). TPO is a cytokine of 353 amino acids composed of an N-terminal domain homologous to Epo and a glycosylated carboxyl domain of unknown function. Recombinant TPO stimulates megakaryocyte proliferation and maturation in vitro from primitive hematopoietic stem cell populations alone or in the presence of other exogenous hematopoietic growth factors (6). TPO induces dramatic increases in platelet production andThe publication costs of this article were defrayed in part by page char...

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Section: Resultsmentioning

confidence: 99%

Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation.

Gurney¹,

Wong²,

Henzel³

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

171

133

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“…The minimal representation of megakaryocytes in the bone marrow, estimated at Ͻ0.5% of the bone marrow cells (1), has hindered the procurement of purified primary cell populations. Human cell lines with megakaryocyte-related characteristics or markers have many shortcomings, including outgrowth from leukemic bone marrow, expression of multiple nonmegakaryocyte lineage markers, and abnormal karyotypes (2). Murine megakaryocyte cell lines are essentially nonexistent.…”

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confidence: 99%

A model for studying megakaryocyte development and biology

Murphy

Leavitt

1999

Proc. Natl. Acad. Sci. U.S.A.

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The limited current understanding of megakaryocyte-lineage development and megakaryocyte biology is in large part because of a paucity of useful systems in which to conduct experiments. To overcome this problem, we have developed a transgenic mouse that uses the GP-Ib␣ regulatory sequences to achieve megakaryocyte-lineage restricted expression of an avian retroviral receptor. Through the transgenic avian receptor, avian retroviruses can efficiently and selectively infect megakaryocyte-lineage cells in vitro and in vivo. Serial infections can be performed to introduce and express multiple genes in the same cell. We have used this system to generate and characterize a pure population of primary CD41-positive megakaryocyte progenitors.

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“…These anuclear cytoplasmic fragments are derived from bone marrow megakaryocytes and are highly differentiated (1). One of the specialized features found on the platelet membrane is the ␣ IIb /␤ 3 (also known as glycoprotein IIb/IIIa or CD41b) integrin receptor (2).…”

mentioning

confidence: 99%

An Sp1-binding Silencer Element Is a Critical Negative Regulator of the Megakaryocyte-specific αIIb Gene

Shou¹,

Baron²,

Poncz³

1998

Journal of Biological Chemistry

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The Sp1 family of transcription factors are often involved in the regulated expression of TATA-less genes, frequently enhancing gene transcription. In this paper, we demonstrate that an Sp1-binding element inhibits the expression of the megakaryocyte-specific ␣ IIb gene in all cell lines tested and that this inhibition is actively overcome only in megakaryocyte-like cell lines. We had noted previously in primary megakaryocytes that a 50-base pair (bp) deletion from ؊150 to ؊101 bp in the rat ␣ IIb promoter region resulted in increased expression. We now show that deletion of this region markedly increased expression in both megakaryocytic and nonmegakaryocytic cell lines, eliminating the tissue specificity of the ␣ IIb promoter. Electrophoretic mobility shift assays (EMSA) defined a single complex, which bound to a ؊145 to ؊125 bp subregion. Point mutations within this region, localized the critical point of binding around bases ؊136/؊135, and expression studies showed that introduction of the ؊136/؊135 mutation into the rat ␣ IIb promoter had a comparable result to that seen with the 50-bp deletion. EMSA studies with the homologous human ␣ IIb promoter region gave an identical migrating band. Southwestern blots of HeLa nuclear proteins with both the rat ؊145 to ؊125 DNA and its human homologue bound to a single ϳ110-kDa protein, the known molecular weight of Sp1. Confirmation that this region of the ␣ IIb gene promoter bound Sp1 was accomplished using EMSA studies with an Sp1 consensus probe, antiSp1 and -Sp3 antibodies, and recombinant Sp1 protein.Further support for the role of Sp1 in the silencing of the ␣ IIb promoter was obtained using a Gal4 binding site substitution for the silencer region of ␣ IIb and co-expression of near full-length Sp1/Gal4 fusion protein expression vectors. Ectopic reinsertion of the ؊150 to ؊101 bp region, back into the ؊150 to ؊101 bp deleted promoter, enhanced rather than decreased expression, suggesting that Sp1's inhibitory role at ؊136/؊135 depends on its local interactions. In summary, we believe that we have identified a cross-species, non-consensus Sp1-binding site that binds Sp1 and that acts as a silencer of ␣ IIb expression in many cell lines. A model is presented as to how this Sp1-binding silencer element contributes to the megakaryocyte-specific expression of ␣ IIb gene.Platelets have a central role in thrombus formation. These anuclear cytoplasmic fragments are derived from bone marrow megakaryocytes and are highly differentiated (1). One of the specialized features found on the platelet membrane is the ␣ IIb /␤ 3 (also known as glycoprotein IIb/IIIa or CD41b) integrin receptor (2). This receptor is densely packed on the platelet surface. Following platelet activation, this receptor binds fibrinogen and plays an important role in platelet aggregation (2). Normally, ␣ IIb /␤ 3 is only found on developing megakaryocytes and circulating platelets. This is due to the tissue-specific nature of the ␣ IIb subunit. While ␤ 3 is expressed in several different cell types (3), ...

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CNS Lupus and the Blood-Brain Barrier

Cited by 15 publications

References 97 publications

Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation.

Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation.

A model for studying megakaryocyte development and biology

An Sp1-binding Silencer Element Is a Critical Negative Regulator of the Megakaryocyte-specific αIIb Gene

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