Signaling by the cytoplasmic domain of hematopoietin receptors involves two distinguishable mechanisms in hepatic cells.
The receptor for granulocyte colony stimulating factor (G-CSFR) and chimeric receptors consisting of the extracellular domain of G-CSFR and the transmembrane and cytoplasmic domain of the leukemia inhibitory factor receptor, gp130, or c-mpl function as homodimeric complexes. These receptors mediate a similar stimulation of gene transcription via separate regulatory elements of acute phase plasma protein genes. To identify the receptor regions within the cytoplasmic domains necessary for transcriptional regulation, the receptors were transiently expressed in rat hepatoma cells. Each receptor form reconstituted G-CSF-induced expression of a chloramphenicol acetyltransferase gene construct containing the cytokine response element of the rat alpha 1-acid glycoprotein gene. This regulation required the presence of two conserved sequence motifs (referred to as box 1 and box 2) in the cytoplasmic domains of each receptor. With the exception of G-CSFR-MPL chimera, the receptors also mediated a similarly high stimulation via the IL-6 response element of the rat beta-fibrinogen and hemopexin genes. Regulation of the IL-6 response element required, however, in addition to boxes 1 and 2, a third sequence motif (box 3). This motif is absent in the cytoplasmic domain of c-mpl, possibly explaining its inability to activate the IL-6 response element. When cells which express receptor forms with prominent box 3 function were treated with suramin, a ligand-independent gene stimulation via the IL-6 response element was observed. The suramin effect probably involves a receptor dimerization mediated by the extracellular G-CSFR domain and by the intracellular regions that include box 3.
Baumann
H
H
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263.
Gearing
D
D
Ziegler
S F
SF
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008099:Liver / Q000378:metabolism*; D008222:Lymphokines; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D008222:Lymphokines; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C082218:MPL protein, human; D013498:Suramin