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Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene.

ABSTRACT: Nerve growth factor (NGF) induces the chromaffin cell line PC12 to differentiate into cells with many of the properties of sympathetic neurons. We investigated the early differentiative phase and identified a gene, PC4, rapidly and transiently induced by NGF in PC12 cells. PC4 cDNA is homologous to the partial sequence of a putative mouse beta-interferon and encodes a protein related to a lymphokine, the rat gamma-interferon protein. Nonetheless, PC4 appears devoid of antiviral activity. PC4 is expressed in proliferating and differentiating tissues, such as amnion, placenta, and brain at embryonic day 13.5. The relationship of PC4 to interferons and lymphokines suggests that it could play a role in regulating gene activity in the pathways induced by NGF.

SUBMITTER: Tirone F

PROVIDER: S-EPMC286853 | biostudies-other | 1989 Mar

REPOSITORIES: biostudies-other

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Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene.

Tirone F F Shooter E M EM

Proceedings of the National Academy of Sciences of the United States of America 19890301 6

Nerve growth factor (NGF) induces the chromaffin cell line PC12 to differentiate into cells with many of the properties of sympathetic neurons. We investigated the early differentiative phase and identified a gene, PC4, rapidly and transiently induced by NGF in PC12 cells. PC4 cDNA is homologous to the partial sequence of a putative mouse beta-interferon and encodes a protein related to a lymphokine, the rat gamma-interferon protein. Nonetheless, PC4 appears devoid of antiviral activity. PC4 is ...[more]

PMID: 2467301

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Project description:BackgroundThe major goal of the study was to compare the genetic programs utilized by the neuropoietic cytokine Interleukin-6 (IL-6) and the neurotrophin (NT) Nerve Growth Factor (NGF) for neuronal differentiation.ResultsThe designer cytokine Hyper-IL-6 in which IL-6 is covalently linked to its soluble receptor s-IL-6R as well as NGF were used to stimulate PC12 cells for 24 hours. Changes in gene expression levels were monitored using Affymetrix GeneChip technology. We found different expression for 130 genes in IL-6- and 102 genes in NGF-treated PC12 cells as compared to unstimulated controls. The gene set shared by both stimuli comprises only 16 genes.A key step is upregulation of growth factors and functionally related external molecules known to play important roles in neuronal differentiation. In particular, IL-6 enhances gene expression of regenerating islet-derived 3 alpha (REG3A; 1084-fold), regenerating islet-derived 3 beta (REG3B/PAPI; 672-fold), growth differentiation factor 15 (GDF15; 80-fold), platelet-derived growth factor alpha (PDGFA; 69-fold), growth hormone releasing hormone (GHRH; 30-fold), adenylate cyclase activating polypeptide (PACAP; 20-fold) and hepatocyte growth factor (HGF; 5-fold). NGF recruits GDF15 (131-fold), transforming growth factor beta 1 (TGFB1; 101-fold) and brain-derived neurotrophic factor (BDNF; 89-fold). Both stimuli activate growth-associated protein 43 (GAP-43) indicating that PC12 cells undergo substantial neuronal differentiation.Moreover, IL-6 activates the transcription factors retinoic acid receptor alpha (RARA; 20-fold) and early growth response 1 (Egr1/Zif268; 3-fold) known to play key roles in neuronal differentiation.Ingenuity biological function analysis revealed that completely different repertoires of molecules are recruited to exert the same biological functions in neuronal differentiation. Major sub-categories include cellular growth and differentiation, cell migration, chemotaxis, cell adhesion, small molecule biochemistry aiming at changing intracellular concentrations of second messengers such as Ca2+ and cAMP as well as expression of enzymes involved in posttranslational modification of proteins.ConclusionThe current data provide novel candidate genes involved in neuronal differentiation, notably for the neuropoietic cytokine IL-6. Our findings may also have impact on the clinical treatment of peripheral nerve injury. Local application of a designer cytokine such as H-IL-6 with drastically enhanced bioactivity in combination with NTs may generate a potent reparative microenvironment.

Dataset Information

Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene.

Publications

Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene.

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