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Thyroid Hormone-Mediated Activation of the ERK/Dual Specificity Phosphatase 1 Pathway Augments the Apoptosis of GH4C1 Cells by Down-Regulating Nuclear Factor-B Activity

Departamento de Bioquímica y Biología Molecular (A.C.), Facultad de Medicina, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain; and Instituto de Investigaciones Biomédicas "Alberto Sols" (Universidad Autónoma de Madrid Consejo Superior de Investigaciones Científicas) (A.S.-P., B.G.-A., A.A., M.L.), 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Marina Lasa, Instituto de Investigaciones Biomédicas "Alberto Sols" (UAM- Consejo Superior de Investigaciones Cienticas), Arturo Duperier 4, 28029 Madrid, Spain. E-mail: mlasa{at}iib.uam.es.

Thyroid hormone (T₃) plays a crucial role in processes such as cell proliferation and differentiation, whereas its implication on cellular apoptosis has not been well documented. Here we examined the effect of T₃ on the apoptosis of GH4C1 pituitary cells and the mechanisms underlying this effect. We show that T₃ produced a significant increase in apoptosis in serum-depleted conditions. This effect was accompanied by a decrease in nuclear factor-B (NF-B)-dependent transcription, IB phosphorylation, translocation of p65/NF-B to the nucleus, phosphorylation, and transactivation. Moreover, these effects were correlated with a T3-induced decrease in the expression of antiapoptotic gene products, such as members of the inhibitor of apoptosis protein and Bcl-2 families. On the other hand, ERK but not c-Jun N-terminal kinase or MAPK p38, was activated upon exposure to T₃, and inhibition of ERK alone abrogated T₃-mediated apoptosis. In addition, T₃ increased the expression of the MAPK phosphatase, dual specificity phosphatase 1 (DUSP1), in an ERK-dependent manner. Interestingly, the suppression of DUSP1 expression abrogated T₃-induced inhibition of NF-B-dependent transcription and p65/NF-B translocation to the nucleus, as well as T₃-mediated apoptosis. Overall, our results indicate that T₃ induces apoptosis in rat pituitary tumor cells by down-regulating NF-B activity through a mechanism dependent on the ERK/DUSP1 pathway.

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Ligands:   Thyroid hormone