Tamoxifen and raloxifene modulate gap junction coupling during early phases of retinoic acid-dependent neuronal differentiation of NTera2/D1 cells |
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Authors: | Liane Dahm Fanny Klugmann Angeles Gonzalez-Algaba Bernhard Reuss |
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Institution: | 1.Center for Anatomy–Neuroanatomy,University of G?ttingen,G?ttingen,Germany |
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Abstract: | Gap junctions (GJ) represent a cellular communication system known to influence neuronal differentiation and survival. To
assess a putative role of this system for neural effects of tamoxifen (TAM) and raloxifene (RAL), we used the human teratocarcinoma
cell line NTera2/D1, retinoic acid (RA)-dependent neuronal differentiation of which is regulated by gap junctions formed of
connexin43 (Cx43). As demonstrated by Western blot analysis, concentrations above 1 μmol/l for TAM, and 0.1 μmol/l for RAL
lead to a temporary time- and concentration-dependent increase in Cx43 immunoreactivity, which reached a peak for TAM after
1 day and for RAL after 2 days. Immunocytochemical stainings revealed the increase in Cx43 immunoreactivity to result from
an accumulation in intracellular compartments such as the Golgi apparatus or lysosomes. In addition, TAM and RAL were able
to prevent the RA-dependent decrease of Cx43 immunoreactivity in NTera2/D1 cells, normally observed during neuronal differentiation.
This suggested a suppression of neuronal differentiation to result from these substances. According to this, treatment of
NTera2/D1 cells with 10 μmol/l TAM or RAL during weeks 1 and 2 of a 6 weeks RA-driven differentiation schedule impaired, whereas
treatment during weeks 5 and 6 did not impair, neuronal differentiation of these cells. Modulation of GJ coupling between
NTera2/D1 cells by TAM and RAL seems therefore to perturb early neuronal differentiation, whereas differentiated neurons in
the mature brain seem to be not affected. These effects could be of importance for actions of TAM and RAL on early embryonic
steps of nervous system formation. |
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