Trans-repression of β-Catenin Activity by Nuclear Receptors

Abstract

The signaling/oncogenic activity of β-catenin can be repressed by the activation of nuclear receptors such as the vitamin A, vitamin D, and androgen receptors. Although these receptors directly interact with β-catenin and can sequester it away from its transcription factor partner T-cell factor, it is not known if this is the mechanism of trans-repression. Using several different promoter constructs and nuclear receptors and mammalian two-hybrid and mutation analyses we now show that interaction with the co-activator, p300, underlies the trans-repression of β-catenin signaling by nuclear receptors and their ligands. The signaling/oncogenic activity of β-catenin can be repressed by the activation of nuclear receptors such as the vitamin A, vitamin D, and androgen receptors. Although these receptors directly interact with β-catenin and can sequester it away from its transcription factor partner T-cell factor, it is not known if this is the mechanism of trans-repression. Using several different promoter constructs and nuclear receptors and mammalian two-hybrid and mutation analyses we now show that interaction with the co-activator, p300, underlies the trans-repression of β-catenin signaling by nuclear receptors and their ligands. By definition, the term chemoprevention refers to the treatment of individuals with premalignant lesions, individuals who are predisposed to the development of malignant lesions, and individuals early in the process of carcinogenesis, with the intention of preventing the later stages of carcinogenesis from developing (1Sporn M.B. Suh N. Nat. Rev. Cancer. 2002; 2: 537-543Crossref PubMed Although such as and are in this is to that the treatment not be in stages of this is not the in and in are to the of and not malignant and in the and of several of are to from this are the that to and is of in nuclear are not by vitamin A, receptors and the to PubMed that such as of the signaling and to its PubMed 2002; PubMed several show that the signaling/oncogenic activity of β-catenin is by the activation of nuclear receptors such as vitamin and androgen receptors PubMed PubMed to its in β-catenin as the factor of transcription Although it is that of these receptors directly interact with β-catenin and sequester it away from it is not known if this is the mechanism of trans-repression. receptors factor and activity by mechanism interaction with of interaction with transcription PubMed PubMed PubMed the in to of β-catenin vitamin and androgen activity as as the of that is not to be of PubMed PubMed Using several different promoter constructs and nuclear mammalian two-hybrid and we now show that interaction with the p300, underlies the trans-repression of β-catenin signaling by nuclear receptors. these that the of to the of is of in trans-repression of activity in to of to of β-catenin PubMed and and by PubMed and its are in PubMed and by PubMed The mammalian two-hybrid to in the β-catenin from and as and with The β-catenin the The and of the by and we to the and of β-catenin and and and and β-catenin with the and the of β-catenin with and of of and by and as and as the to the from in the and in in with and in with the of with with and in in and in and with of the with of and and of treatment activity the The activity by with the mammalian two-hybrid and with as to in the of and in The with by and the by The in and in of and to in we that signaling activity be by in and and in and PubMed these to by and activation of and PubMed PubMed not to by to in these PubMed to the of these to to by with of trans-repression of β-catenin that to be to the of PubMed and and of β-catenin as of mutation in the mutation of that these treatment with and and of and and and and 2: PubMed signaling by treatment in and in that the of these to in to is with the of to β-catenin of to with in that trans-repression of β-catenin signaling by not in the of β-catenin the of the 2002; 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Suh N. Nat. Rev. Cancer. 2002; 2: 537-543Crossref PubMed Although such as and are in this is to that the treatment not be in stages of this is not the in and in are to the of and not malignant and in the and of several of are to from this are the that to and is of in nuclear are not by vitamin A, receptors and the to PubMed that such as of the signaling and to its PubMed 2002; PubMed vitamin androgen factor T-cell factor vitamin androgen factor T-cell factor several show that the signaling/oncogenic activity of β-catenin is by the activation of nuclear receptors such as vitamin and androgen receptors PubMed PubMed to its in β-catenin as the factor of transcription Although it is that of these receptors directly interact with β-catenin and sequester it away from it is not known if this is the mechanism of trans-repression. receptors factor and activity by mechanism interaction with of interaction with transcription PubMed PubMed PubMed the in to of β-catenin vitamin and androgen activity as as the of that is not to be of PubMed PubMed Using several different promoter constructs and nuclear mammalian two-hybrid and we now show that interaction with the p300, underlies the trans-repression of β-catenin signaling by nuclear receptors. these that the of to the of is of in trans-repression of activity in to of to of β-catenin PubMed and and by PubMed and its are in PubMed and by PubMed The mammalian two-hybrid to in the β-catenin from and as and with The β-catenin the The and of the by and we to the and of β-catenin and and and and β-catenin with the and the of β-catenin with and of of and by and as and as the to the from in the and in in with and in with the of with with and in in and in and with of the with of and and of treatment activity the The activity by with the mammalian two-hybrid and with as to in the of and in The with by and the by The in and in of β-catenin PubMed and and by PubMed and its are in PubMed and by PubMed The mammalian two-hybrid to in the β-catenin from and as and with The β-catenin the The and of the by and we to the and of β-catenin and and and and β-catenin with the and the of β-catenin with and of of and by and as and as the to the from in the and in in with and in with the of with with and in in and in and with of the with of and and of treatment activity the The activity by with the mammalian two-hybrid and with as to in the of and in The with by and the by The in and in of and to in we that signaling activity be by in and and in and PubMed these to by and activation of and PubMed PubMed not to by to in these PubMed to the of these to to by with of trans-repression of β-catenin that to be to the of PubMed and and of β-catenin as of mutation in the mutation of that these treatment with and and of and and and and 2: PubMed signaling by treatment in and in that the of these to in to is with the of to β-catenin of to with in that trans-repression of β-catenin signaling by not in the of β-catenin the of the 2002; 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