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Background  INhibitor of Growth (ING) proteins belong to a large family of plant homeodomain finger-containing proteins important in epigenetic regulation and carcinogenesis. We have previously shown that  ING1  and  ING2  expression is regulated by thyroid hormone (TH) during metamorphosis of the  Xenopus laevis  tadpole. The present study investigates the possibility that ING proteins modulate TH action.    Methodology/Principal Findings  Tadpoles expressing a  Xenopus ING2  transgene (Trans ING2 ) were significantly smaller than tadpoles not expressing the transgene (Trans GFP ). When exposed to 10 nM 3,5,3′-triiodothyronine (T 3 ), premetamorphic Trans ING2  tadpoles exhibited a greater reduction in tail, head, and brain areas, and a protrusion of the lower jaw than T 3 -treated Trans GFP  tadpoles. Quantitative real time polymerase chain reaction (QPCR) demonstrated elevated  TH receptor β  ( TRβ ) and  TH/bZIP  transcript levels in Trans ING2  tadpole tails compared to Trans GFP  tadpoles while  TRα  mRNAs were unaffected. In contrast, no difference in  TRα ,  TRβ  or  insulin-like growth factor  ( IGF2)  mRNA abundance was observed in the brain between Trans ING2  and Trans GFP  tadpoles. All of these transcripts, except for  TRα  mRNA in the brain, were inducible by the hormone in both tissues. Oocyte transcription assays indicated that ING proteins enhanced TR-dependent, T 3 -induced  TRβ  gene promoter activity. Examination of endogenous T 3 -responsive promoters ( TRβ  and  TH/bZIP ) in the tail by chromatin immunoprecipitation assays showed that ING proteins were recruited to TRE-containing regions in T 3 -dependent and independent ways, respectively. Moreover, ING and TR proteins coimmunoprecipitated from tail protein homogenates derived from metamorphic climax animals.    Conclusions/Significance  We show for the first time that ING proteins modulate TH-dependent responses, thus revealing a novel role for ING proteins in hormone signaling. This has important implications for understanding hormone influenced disease states and suggests that the induction of ING proteins may facilitate TR function during metamorphosis in a tissue-specific manner.

Modulation of Thyroid Hormone-Dependent Gene Expression in Xenopus laevis by INhibitor of Growth (ING) Proteins