The adenoviral E1A protein displaces corepressors and relieves gene repression by unliganded thyroid hormone receptors in vivo

Abstract

The human adenovirus type 5 early region 1A (E1A) is one of two oncogenes present in the adenovirus genome and functions by interfering with the activities of cellular regulatory proteins. The E1A gene is alternatively spliced to yield five products. Earlier studies have revealed that E1A can regulate the function of thyroid hormone (T3) receptors (TRs). However, analysis in yeast compared with transfection studies in mammalian cell cultures yields surprisingly different effects. Here, we have examined the effect of E1A on TR function by using the frog oocyte in vivo system, where the effects of E1A can be studied in the context of chromatin. We demonstrate that different isoforms of E1A have distinct effects on TR function. The two longest forms inhibit both the repression by unliganded TR and activation by T3-bound TR. We further show that E1A binds to unliganded TR to displace the endogenous corepressor nuclear receptor corepressor, thus relieving the repression by unliganded TR. On the other hand, in the presence of T3, E1A inhibits gene activation by T3-bound TR indirectly, through a mechanism that requires its binding domain for the general coactivator p300. Taken together, our results thus indicate that E1A affects TR function through distinct mechanisms that are dependent upon the presence or absence of T3.

Dual Functions of Thyroid Hormone Receptors in Vertebrate Development: The Roles of Histone-Modifying Cofactor Complexes

“…1A). Many TR-interacting proteins have been isolated and characterized through in vitro and cell culture studies (2,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Two highly related proteins N-CoR (nuclear corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) are among the best-studied TR-binding corepressors.…”

Molecular and genetic studies suggest that thyroid hormone receptor is both necessary and sufficient to mediate the developmental effects of thyroid hormone

“…TR functions by recruiting cofactors. Many such cofactors have been isolated and characterized (Burke and Baniahmad, 2000; Glass and Rosenfeld, 2000; Huang et al, 2003; Ito and Roeder, 2001; Jones and Shi, 2003; McKenna et al, 1999; McKenna and O'Malley, 2001; Meng et al, 2003; Rachez and Freedman, 2000; 2001; Sato et al, 2009; Wahlstrom et al, 1999; Xu et al, 1999; Zhang and Lazar, 2000). In the absence of TH, TR recruits corepressors, such as the highly related proteins SMRT and N-CoR, which form multimeric complexes containing histone deacetylases (HDACs) (Burke and Baniahmad, 2000; Glass and Rosenfeld, 2000; Jones and Shi, 2003; Zhang and Lazar, 2000) (Fig.…”

Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival

“…Interestingly, the N‐terminal domain of E1As contains a conserved sequence motif that resembles the hydrophobic NR‐interacting sequence found in corepressors (CoRs) such as NCORs. Through this motif, E1As can compete against CoRs for binding to NRs, thereby promoting NR activation …”

“…Through this motif, E1As can compete against CoRs for binding to NRs, thereby promoting NR activation. 30,31 There are >50 serotypes of human adenoviruses. These viruses display marked genetic diversity and clinical phenotypes.…”