Accumulated evidence suggests that
thyroid hormone receptor β (TRβ) could function as a
tumor suppressor, but the detailed mechanisms by which TRβ inhibits
tumorigenesis are not fully understood. The present studies explored the mechanisms by which TRβ acted to inhibit thyroid
tumor development mediated by simian virus-40 (SV40). In mouse xenograft models, SV40
large T antigen (SV40Tag)-immortalized human thyroid epithelial (HTori) cells rapidly induced
tumors, but the
tumor development was totally blocked by TRβ stably expressed in HTori cells. Previous studies showed that the SV40Tag
oncoprotein binds to and inactivates
tumor suppressors p53 and
retinoblastoma protein (Rb), thereby inducing
tumorigenesis. Here we showed that one of the mechanisms by which TRβ suppressed
tumor development was by competing with p53 and Rb for binding to SV40Tag. The interaction of TRβ with SV40Tag led to reactivation of Rb to inhibit cell cycle progression. TRβ- SV40Tag interaction also resulted in reactivating p53 to increase the expression of Pten, thus attenuating PI3K-AKT signaling to decrease cell proliferation and to induce apoptosis. The present study uncovered a novel action of TRβ as a
tumor suppressor initiated via interfering with the recruitment of Rb and p53 by SV40Tag
oncoprotein through
protein-
protein interaction, thereby acting to block
tumor development.