REGULATION OF NGF RESPONSIVENESS IN HUMAN NEUROBLASTOMA

Functional nerve growth factor (NGF) responsiveness was investigated i n human neuroblastoma (NB) cell lines ill vitro and retinoic acid (RA) was found to transcriptionally enhance expression of the trkA, but no t the trkB gene in GOTO cells, while the reverse was found in HTLA230 NE cells. Ciliary neurotrophic factor (CNTF) specifically induced trkA gene transcription in both cell lines. Transcriptional activation of the trkA gene increased total trkA protein and surface bound receptor, which was tyrosine phosphorylated upon NGF stimulation inducing immed iate early response gene transcription (i.e. c-fos, Egr-1). Newly synt hesized trkA protein had a molecular weight of 110 kDa and was post-tr anslationally modified. Rapid down regulation of the receptor protein occurred upon NGF stimulation, despite the presence of high levels of trkA mRNA, due to an increased rate of receptor degradation. Transient DNA synthesis and cell proliferation upon NGF treatment occurred in G OTO cells with elevated trkA expression. In contrast, NGF induced neur onal differentiation in HTLA230 cells expressing the endogenous trkA r eceptor gene, despite the lack of p75 expression. Hence, transcription al activation of trkA gene expression can be achieved by different sig nal pathways in human NE cells, but NGF can act either as mitogen or i nducer of cell differentiation, depending on the tumor from which cell s are derived.