Abstract
Trk receptors are a family of genes implicated in the survival, differentiation, and growth of certain neurons and tumors of the nervous system. A better understanding of the regulation of Trk receptors is relevant for developmental and oncological studies. Human neuroblastoma (NB) cell lines constitutively express low levels of TrkA mRNA, while TrkB mRNA is not readily detectable. Differentiation of NB cells is accompanied by a differential modulation of Trk expression in human NB cells. Nanomolar concentrations of RA induce a stable increase of TrkB mRNA. A transient induction of TrkA mRNA levels requires micromolar concentrations of RA. Induction of both TrkA and TrkB mRNA does not require new protein synthesis. However, RA-induced TrkB mRNA expression is transcriptionally regulated, while the transient RA-induced increase of TrkA mRNA is a consequence of extended mRNA stability. Interferon gamma (IFN-gamma) selectively increases TrkA mRNA without affecting TrkB mRNA levels. Similar to RA, IFN-gamma does not modify the transcriptional rate of TrkA mRNA, but rather increases TrkA mRNA stability. Thus, RA and IFN-gamma differentially regulate TrkA or TrkB expression in the same cell type by predominantly transcriptional (TrkB) or post transcriptional (TrkA) mechanisms. Such experiments indicate the complexity of Trk mRNA regulation and also indicate compounds that may affect neurotrophin responsiveness in developing neural cells.
Highlights
Trk receptors are a family of genes implicated in the survival, differentiation, and growth of certain neurons and tumors of the nervous system
Kinetics of Trk mRNA Expression in RA-treated KCNR Cells—Previous studies indicated that RA increased TrkB but not TrkA mRNA expression in KCNR NB cells when evaluated at 8 days (Kaplan et al, 1993)
In order to determine the kinetics of RA-induced TrkA and TrkB mRNA expression, the NB cell line KCNR was treated with 5 M RA or control solvent and TrkA and TrkB mRNA expression was evaluated after 3, 6, and 9 days of treatment
Summary
Vol 270, No 42, Issue of October 20, pp. 24725–24731, 1995 Printed in U.S.A. Selective Regulation of TrkA and TrkB Receptors by Retinoic Acid and Interferon-␥ in Human Neuroblastoma Cell Lines*. RA and IFN-␥ differentially regulate TrkA or TrkB expression in the same cell type by predominantly transcriptional (TrkB) or post transcriptional (TrkA) mechanisms Such experiments indicate the complexity of Trk mRNA regulation and indicate compounds that may affect neurotrophin responsiveness in developing neural cells. The observation that the survival dependence of trigeminal neurons switches from BDNF to NT3 or NGF during development implies that specific neural populations may change their pattern of Trk receptors expression (Buchman et al, 1993; Verdi et al, 1994) Such studies indicate that a complex set of environmental signals must be coordinated to regulate Trk expression. IFNs regulate the expression of several genes at either the transcriptional or post-transcriptional levels, such as the 2–5A synthetase that induce cell resistance to viruses, and interleukins that control growth and differentiation of many types of cells (Vilcek et al, 1994). We examine TrkA and TrkB gene regulation in both the presence and absence of RA or IFN-␥ and describe distinct mechanisms of regulation of these genes
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