High-level expression of receptor tyrosine kinase Ret and responsiveness to Ret-activating ligands in pheochromocytoma cell lines from neurofibromatosis knockout mice.
Pheochromocytoma cell lines derived from neurofibromatosis knockout mice express high levels of the receptor tyrosine kinase Ret, which is involved in the pathogenesis of human pheochromocytomas in hereditary multiple endocrine neoplasia syndrome type 2 (MEN2). Mouse pheochromocytoma (MPC) cells respond to the Ret-activating ligand GDNF by exhibiting Ret phosphorylation, neurite outgrowth, decreased proliferation, and altered expression of catecholamine biosynthetic enzymes. GDNF exerts similar effects on human pheochromocytoma cells in primary cultures. Ret is minimally expressed by normal mouse chromaffin cells, from which pheochromocytomas are derived. Its expression at high levels by MPC cells suggests possible relationships between two previously unrelated tumor syndromes, neurofibromatosis, and MEN2. The responsiveness of these cells to GDNF suggests that they may be a valuable new model for neurobiology.
Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel. jpowers@lifespan.org
James F
JF
Powers
Kimberley
K
Schelling
Jaime M
JM
Brachold
Panayiotis
P
Tsokas
Hagit
H
Schayek
Eitan
E
Friedman
Arthur S
AS
Tischler
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000627:therapeutic use; D017253:Neurofibromatoses / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*
D029721:Drosophila Proteins; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat