TRbeta is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells.
OBJECTIVE
Thyroid hormones elicit many cellular and metabolic effects in various organs. Most of these actions, including mitogenesis, are mediated by the thyroid hormone 3,5,3'-triiodo-l-thyronine (T3) nuclear receptors (TRs). They are transcription factors, expressed as different isoforms encoded by the TRalpha and TRbeta genes. Here, experiments were performed to determine whether (i) T3-induces hepatocyte proliferation in mouse liver and pancreas, and, (ii) which TR isoform, is responsible for its mitogenic effect.


METHODS
Cell proliferation was measured by bromodeoxyuridine (BrdU) incorporation after T3 or the TRbeta agonist GC-1 in liver and pancreas of CD-1, C57BL, or TRalpha(0/0) mice. Cell cycle-associated proteins were measured by Western blot.


RESULTS
T3 added to the diet at a concentration of 4 mg/kg caused a striking increase in BrdU incorporation in mouse hepatocytes. Increased BrdU incorporation was associated with enhanced protein levels of cyclin D1 and PCNA and decreased levels of p27. Treatment with GC-1, a selective agonist of the TRbeta isoform, also induced a strong mitogenic response of mouse hepatocytes and pancreatic acinar cells which was similar to that elicited by T3. Finally, treatment with T3 of mice TRalpha(0/0) induced a proliferative response in the liver and pancreas, similar to that of their wild type counterpart.


CONCLUSIONS
These results demonstrate that T3 is a powerful inducer of cell proliferation in mouse liver and suggest that the beta-isoform is responsible for the hepatomitogenic activity of T3. The same isoform seems to also mediate the proliferation of mouse pancreatic acinar cells.
Kowalik
Marta A
MA
Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy.
Perra
Andrea
A
Pibiri
Monica
M
Cocco
Maria T
MT
Samarut
Jacques
J
Plateroti
Michelina
M
Ledda-Columbano
Giovanna M
GM
Columbano
Amedeo
A
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology*
D020033:Protein Isoforms; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine