The Department of Genetic Medicine at Weill Cornell leads a dynamic and innovative translational research program, advancing diverse fields such as Genetic Therapy and Personalized Medicine.
Our translational research program aims to leverage our expertise in genetic therapies and personalized medicine to develop clinical solutions that target the molecular causes of human diseases.
The Department of Genetic Medicine advances treatments and diagnostics through diverse clinical trials, including drug testing and research to better understand diseases.
The Department of Genetic Medicine at Weill Cornell leads a dynamic and innovative translational research program, advancing diverse fields such as Genetic Therapy and Personalized Medicine.
Our translational research program aims to leverage our expertise in genetic therapies and personalized medicine to develop clinical solutions that target the molecular causes of human diseases.
The Department of Genetic Medicine advances treatments and diagnostics through diverse clinical trials, including drug testing and research to better understand diseases.
Regulation of insulin-like growth factor I gene expression in the human macrophage-like cell line U937.
Publication Type
Academic Article
Authors
Nagaoka I, Trapnell B, Crystal R
Journal
J Clin Invest
Volume
85
Issue
2
Pagination
448-55
Date Published
02/01/1990
ISSN
0021-9738
Keywords
Gene Expression Regulation, Insulin-Like Growth Factor I, Macrophages, Somatomedins
Abstract
Activated macrophages release tissue forms of insulin-like growth factor I (IGF-I), 20-25-kD products of the IGF-I gene, thus providing an extracellular growth and differentiation signal at sites of inflammation. To examine the control of IGF-I gene expression in mononuclear phagocytes, the human macrophage-like cell line U937 was evaluated at rest and after surface activation with phorbol myristate acetate (PMA) or Ca2+ ionophore. Northern analysis and RNAse protection analysis with 32P-labeled IGF-I-specific probes demonstrated that the IGF-I mRNA transcripts of resting U937 cells were similar in size and amount to those of resting human alveolar macrophages, mononuclear phagocytes known to express the IGF-I gene. Nuclear run-off assays demonstrated that surface activation of U937 cells increased the transcription rate of the IGF-I gene four- to fivefold, a process that was inhibited by cycloheximide, suggesting that active protein synthesis was involved in the activation pathway. Despite this, cytoplasmic IGF-I mRNA levels after surface activation declined markedly, a process blocked by a protein kinase C inhibitor (for PMA activation) or a calmodulin antagonist (for Ca2+ ionophore activation). Like the increased transcription of the IGF-I gene, modulation of IGF-I mRNA transcript levels required active protein synthesis; in the presence of cycloheximide constitutive IGF-I mRNA levels increased and surface activation no longer caused a decrease in transcript number. Interestingly, surface activation caused a rapid release of IGF-I, even in the presence of a protein synthesis inhibitor, suggesting that mononuclear phagocytes have a preformed, stored, releasable pool of IGF-I. Together these observations demonstrate that IGF-I gene expression is complex and probably involves control of transcription rate, cytoplasmic mRNA levels possibly mediated through protein kinase C, calcium influx and calmodulin, and finally, release of preformed IGF-I from a storage pool.