Complex conserved organization of the mammalian leukemia inhibitory factor gene: regulated expression of intracellular and extracellular cytokines.
Leukemia inhibitory factor (LIF) is a member of the IL-6 family of pleiotropic cytokines, which are extensively involved in modulating hematopoiesis and immunity. We have undertaken a detailed analysis of LIF genomic organization and gene transcription and investigated the proteins expressed from alternate transcripts. Previously unidentified LIF transcripts, containing alternate first exons spliced onto common second and third exons, were cloned from murine embryonic stem cells, human embryonal carcinoma cells, and primary porcine fibroblasts. Based on sequence homology and position within the genomic sequence, this confirmed the existence of the LIF-M transcript in species other than the mouse and identified a new class of transcript, designated LIF-T. Thus, a complex genomic organization of the LIF gene, conserved among eutherian mammals, results in the expression of three LIF transcripts (LIF-D, LIF-M, and LIF-T) differentially expressed from alternate promoters. The first exon of the LIF-T transcript contained no in-frame AUG, causing translation to initiate downstream of the secretory signal sequence at the first AUG in exon two, producing a truncated LIF protein that was localized within the cell. Enforced secretion of this protein demonstrated that it could act as a LIF receptor agonist. Regulated expression of biologically active intracellular and extracellular LIF cytokine could thus provide alternate mechanisms for the modulation of hematopoiesis and immune system function.
Haines
B P
BP
Department of Biochemistry, University of Adelaide, Australia.
Voyle
R B
RB
Pelton
T A
TA
Forrest
R
R
Rathjen
P D
PD
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006131:Growth Inhibitors / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015850:Interleukin-6; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D008970:Molecular Weight; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D012689:Sequence Homology, Nucleic Acid; D013552:Swine; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured
D016207:Cytokines; 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; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF