SELECTIVE REGULATION OF TRKA AND TRKB RECEPTORS BY RETINOIC ACID AND INTERFERON-GAMMA IN HUMAN NEUROBLASTOMA CELL-LINES

Trk receptors are a family of genes implicated in the survival, differ entiation, and growth of certain neurons and tumors of the nervous sys tem. A better understanding of the regulation of Trk receptors is rele vant for developmental and oncological studies. Human neuroblastoma (N B) cell lines constitutively express low levels of TrkA mRNA, while Tr kB mRNA is not readily detectable. Differentiation of NB cells is acco mpanied by a differential modulation of Trk expression in human NE cel ls. Nanomolar concentrations of RA induce a stable increase of TrkB mR Nk. A transient induction of TrkA mRNA levels requires micromolar conc entrations of RA. Induction of both TrkA and TrkB mRNA does not requir e new protein synthesis. However, RA-induced TrkB mRNA expression is t ranscriptionally regulated, while the transient RA-induced increase of TrkA mRNA is a consequence of extended mRNA stability. Interferon gam ma (IFN-gamma) selectively increases TrkA mRNA without affecting TrkB mRNA levels. Similar to RA, IFN-gamma does not modify the transcriptio nal rate of TrkA mRNA, but rather increases TrkA mRNA stability. Thus, RA and IFN-gamma differentially regulate TrkA or TrkB expression in t he same cell type by predominantly transcriptional (TrkB) or post tran scriptional (TrkA) mechanisms. Such experiments indicate the complexit y of Trk mRNA regulation and also indicate compounds that may affect n eurotrophin responsiveness in developing neural cells.