The c-erbA alpha protooncogene induces apoptosis in glial cells via a protein kinase C- and bcl-2-suppressible mechanism.
The c-erbA protooncogene encodes the thyroid hormone (3,5,3'-triiodothyronine; T3) receptor alpha1 (TR alpha1). c-erbA/TR alpha1 is expressed in many cell types including glial cells, particularly in the immature state. We show here by morphological and biochemical criteria that c-erbA induces apoptosis of glial B3.1 cells in serum-deprived conditions. This effect is mostly T3 independent. Growth factors such as platelet-derived growth factor, basic fibroblast growth factor, or transforming growth factor-alpha prevent B3.1 + TR alpha1 cell death. Protein kinase C (PKC) activators also prevent the apoptosis phenomenon, an effect that was blocked by the PKC-specific inhibitor GF109203X. Expression of an exogenous bcl-2 gene led also to B3.1 + TR alpha1 cell survival. Neither a series of inhibitors including GF109203X nor T3 inhibits bcl-2 action, indicating that bcl-2 blocks a downstream step in the death-promoting process. B3.1 + TR alpha1 cell apoptosis is not blocked by caspase-1 or poly-ADP-ribosyltransferase inhibitors, suggesting that the activation of these classic pathways is not involved in the apoptotic mechanism. In addition, direct interaction with specific neuronal cells but not incubation with their conditioned medium inhibits also apoptosis of B3.1 + TR alpha1 cells. Our results show that c-erbA promotes an apoptotic process in glial B3.1 cells that is suppressible by PKC activation and bcl-2, probably by distinct mechanisms.
Llanos
S
S
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Caelles
C
C
Azorín
I
I
Renau-Piqueras
J
J
Fernández-Luna
J L
JL
Boscá
L
L
Muñoz
A
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D051379:Mice; D009457:Neuroglia / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014284:Triiodothyronine / Q000378:metabolism
D016895:Culture Media, Serum-Free; D010982:Platelet-Derived Growth Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011988:Receptors, Thyroid Hormone; D018808:Transcription Factor AP-1; D014284:Triiodothyronine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate