Transcriptional regulation of the human glycoprotein hormone common alpha subunit gene by cAMP-response-element-binding protein (CREB)-binding protein (CBP)/p300 and p53.
We have investigated the functional interactions between adenovirus early region 1A (AdE1A) protein, the co-activators cAMP-response-element-binding protein (CREB)-binding protein (CBP)/p300 and SUG1, and the transcriptional repressor retinoblastoma (Rb) in mediating T3-dependent repression. Utilizing the human glycoprotein hormone common alpha-subunit (alpha-subunit) promoter and AdE1A mutants with selective binding capacity to these molecules we have determined an essential role for CBP/p300. In normal circumstances, wild-type 12 S AdE1A inhibited alpha-subunit activity. In contrast, adenovirus mutants that retain both the SUG1- and Rb-binding sites, but lack the CBP/p300-binding site, were unable to repress promoter activity. We have also identified a role for the tumour-suppressor gene product p53 in regulation of the alpha-subunit promoter. Akin to 12 S AdE1A, exogenous p53 expression repressed alpha-subunit activity. This function resided in the ability of p53 to interact with CBP/p300; an N-terminal mutant incapable of interacting with CBP/p300 did not inhibit alpha-subunit activity. Stabilization of endogenous p53 by UV irradiation also correlated positively with reduced alpha-subunit activity. Intriguingly, T3 stimulated endogenous p53 transcriptional activity, implicating p53 in T3-dependent signalling pathways. These data indicate that CBP/p300 and p53 are key regulators of alpha-subunit activity.
Zhang
Xian
X
Cancer Research U.K. Institute for Cancer Studies, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Grand
Roger J A
RJ
McCabe
Christopher J
CJ
Franklyn
Jayne A
JA
Gallimore
Phillip H
PH
Turnell
Andrew S
AS
D000256:Adenoviridae / Q000235:genetics; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D015292:Glycoprotein Hormones, alpha Subunit; D009687:Nuclear Proteins; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53