Faculty Collaboration Database

GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice. Exp Cell Res 2005 Feb 01;303(1):79-88

Date

12/02/2004

Pubmed ID

15572029

DOI

10.1016/j.yexcr.2004.09.028

Scopus ID

2-s2.0-9644295588 (requires institutional sign-in at Scopus site)   16 Citations

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.

Author List

Park JI, Powers JF, Tischler AS, Strock CJ, Ball DW, Nelkin BD

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Butadienes
Cell Differentiation
GAP-43 Protein
Genes, ras
Glial Cell Line-Derived Neurotrophic Factor
Interleukin-6
Intracellular Signaling Peptides and Proteins
Leukemia Inhibitory Factor
MAP Kinase Kinase 1
MAP Kinase Kinase Kinase 2
Mice
Mice, Knockout
Mitogen-Activated Protein Kinases
Nerve Growth Factors
Neurites
Neurofibromin 1
Nitriles
Pheochromocytoma
Proteins
Tumor Cells, Cultured