title: GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice.
abstract: Glial cell line-derived neurotrophic factor (GDNF) can induce neuron-like differentiation of mouse pheochromocytoma (MPC) cell lines derived from mice with a heterozygous knockout mutation of nf1, the murine counterpart of the human gene mutated in neurofibromatosis type 1 (NF1). Here, we show that GDNF-induced differentiation in the MPC 862L cell line is mediated by the MEK/extracellular signal-regulated kinase (ERK) pathway. Neurite outgrowth, increased expression of growth-associated protein 43, and decreased incorporation of bromodeoxyuridine (BrdU) were induced by treatment with GDNF, H-RasV12, or a constitutively active MEK2. GDNF also induces leukemia inhibitory factor (LIF) via the MEK/ERK pathway, and LIF itself can elicit these differentiative changes via a cell-extrinsic autocrine/paracrine pathway. Treatment with anti-LIF neutralizing antibody depleted the differentiative activity of the conditioned medium from cells stimulated for MEK/ERK signaling, while recombinant LIF could induce differentiation in MPC cells, indicating that LIF is the sole factor with differentiative activity. LIF could activate MEK1/2 and STAT3, but LIF-induced differentiation was blocked only by the MEK1/2-specific inhibitor U0126, indicating that the MEK/ERK pathway is necessary for LIF action in MPC cells. Our findings suggest that LIF may be utilized for signaling mediated by GDNF and may be important in the pathobiology of neuroendocrine tumors.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. jpark15@jhmi.edu
authors.forename: Jong-In
authors.initials: JI
authors.lastname: Park
authors.forename: James F
authors.initials: JF
authors.lastname: Powers
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Strock
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Ball
authors.forename: Barry D
authors.initials: BD
authors.lastname: Nelkin
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D019922:GAP-43 Protein; D011905:Genes, ras / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010673:Pheochromocytoma / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D002070:Butadienes; D019922:GAP-43 Protein; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009414:Nerve Growth Factors; D025542:Neurofibromin 1; D009570:Nitriles; D011506:Proteins; C113580:U 0126; C015482:protein kinase modulator; D020928:Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; D048369:MAP Kinase Kinase 1