The TRbeta1 is essential in mediating T3 action on Akt pathway in human pancreatic insulinoma cells.
Thyroid hormone action, widely recognized on cell proliferation and metabolism, has recently been related to the phosphoinositide 3 kinase (PI3K), an upstream regulator of the Akt kinase and the involvement of the thyroid hormone receptor beta1 has been hypothesized. The serine-threonine kinase Akt can regulate various substrates that drive cell mass proliferation and survival. Its action has also been characterized in pancreatic beta-cells. We previously demonstrated that Akt activity and its activation in the insulinoma cell line hCM could be considered a specific target of the non-genomic action of T3. In this study we analyzed the molecular pathways involved in the regulation of cell proliferation, survival, size, and protein synthesis by T3 in a stable TRbeta1 interfered insulinoma cell line, derived from the hCM, and evidenced a strong regulation of both physiological and molecular events by T3 mediated by the thyroid hormone receptor beta1. We showed that the thyroid receptor beta1 mediates the T3 regulation of the cdk4.cyc D1.p21(CIP1).p27(KIP1) complex formation and activity. In addition TRbeta1 is essential for the T3 upregulation of the Akt targets beta-catenin, p70S6K, and for the phosphorylation of Bad and mTOR. We demonstrated that the beta1 receptor mediates the T3 upregulation of protein synthesis and cell size, together with the cell proliferation and survival, playing a crucial role in the T3 regulation of the PI3K/Akt pathway.
Verga Falzacappa
Cecilia
C
II Faculty of Medicine, Sapienza University of Rome, Rome, Italy.
Patriarca
Valentina
V
Bucci
Barbara
B
Mangialardo
Claudia
C
Michienzi
Simona
S
Moriggi
Giulia
G
Stigliano
Antonio
A
Brunetti
Ercole
E
Toscano
Vincenzo
V
Misiti
Silvia
S
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048429:Cell Size; D002470:Cell Survival; D006801:Humans; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*; D014284:Triiodothyronine / Q000378:metabolism*
D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D051057:Proto-Oncogene Proteins c-akt