Induction of Egr-1 by oncostatin M precedes up-regulation of low density lipoprotein receptors in HepG2 cells.
Oncostatin M (OM), a 28 kilodalton glycoprotein cytokine, is structurally and functionally related to interleukin 6 and leukemia-inhibitory factor. We reported previously that OM strongly up-regulated low density lipoprotein (LDL) receptors in human liver cells by a tyrosine kinase-mediated mechanism. Now, we demonstrate that the transcription factor Egr-1 is induced by OM. The induction of Egr-1 was time and concentration dependent; maximal inductions of 10-fold occurred by 30 min at concentrations of 10-25 ng/ml and higher. This concentration dependency was identical to those for OM-mediated tyrosine phosphorylation and LDL receptor up-regulation. The Egr-1, tyrosine kinase, and LDL receptor responses were inhibited at similar concentrations of genistein, suggesting that induction of Egr-1 and up-regulation of LDL receptors depended on activation of tyrosine kinase by OM. In contrast, depletion of protein kinase C by preincubation with 4 beta-phorbol 12-myristate 13 alpha-acetate did not affect OM-mediated induction of Egr-1 or up-regulation of LDL receptors, indicating that protein kinase C is not required for the OM action. Other similar cytokines were investigated, and, of these, only interleukin 1 could increase both Egr-1 and LDL receptor activity. The correlation among tyrosine kinase phosphorylation, Egr-1 induction, and LDL receptor regulation suggests that Egr-1 may be a nuclear signal transducer utilized by OM to induce transcription of the LDL receptor gene. In support of this possibility is the discovery of an Egr-1 consensus sequence (GAGGGGGCG) at approximately 330 base pairs upstream from the transcription initiation site of the LDL receptor promoter region.
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
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Liu
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M
Shoyab
R I
RI
Grove
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D051766:Early Growth Response Protein 1; D006801:Humans; D017874:Immediate-Early Proteins; D008113:Liver Neoplasms / Q000378:metabolism*; D008969:Molecular Sequence Data; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D011973:Receptors, LDL / Q000187:drug effects*; D014157:Transcription Factors / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D016335:Zinc Fingers
D016207:Cytokines; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; C508351:OSM protein, human; D010455:Peptides; D011973:Receptors, LDL; D014157:Transcription Factors; D053683:Oncostatin M