The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction.
The neuron-like differentiation of PC12 cells is induced by nerve growth factor (NGF) through stimulation of a membrane-bound protooncoprotein signaling pathway containing the NGF receptor Trk, the tyrosine kinase Src, and the GTP-binding protein Ras. The Raf-1 and B-raf protooncogenes encode cytoplasmic serine/threonine kinases that are stimulated by NGF in a Ras-dependent manner. To investigate the possible roles of cytoplasmic Raf kinases in eliciting neuronal differentiation, we have expressed the activated Raf-1 oncogene in PC12 cells. Expression of the raf oncogene results in the elaboration of a neuron-like phenotype, including neurite growth and the induction of the NGF-responsive genes NGFI-A and transin. The actions of activated Raf-1 and NGF are not additive. Furthermore, activated Raf-1 oncoprotein can prime cells for transcription-independent neurite growth by NGF and can elicit rapid neurite growth from NGF-primed cells. Our data indicate that the pathways utilized by NGF and activated raf to effect PC12 differentiation overlap and lead to the suggestion that cellular raf kinase activities play significant roles in transducing the differentiating signals of neuronal growth factors.
Wood
K W
KW
Department of Cellular and Molecular Biology, Dana-Farber Cancer Institute, Boston, MA 02115.
Qi
H
H
D'Arcangelo
G
G
Armstrong
R C
RC
Roberts
T M
TM
Halegoua
S
S
D000818:Animals; D015152:Blotting, Northern; D002999:Clone Cells; D003907:Dexamethasone / Q000494:pharmacology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D027384:Oncogene Proteins v-raf; D009857:Oncogenes; D016716:PC12 Cells; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D009414:Nerve Growth Factors; D015682:Retroviridae Proteins, Oncogenic; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D027384:Oncogene Proteins v-raf