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Cited2, an autoregulated transcriptional modulator, in TGF-beta signaling
| Title: | Cited2, an autoregulated transcriptional modulator, in TGF-beta signaling |
| Author: | Chou, Yu-Ting |
| Description: | Cited2 [CBP/p300 interacting transactivator with E (Glutamic acid) and D (Aspartic acid) rich C-terminal domain, 2] is a CBP/p300 binding transcription factor without typical DNA binding domains. Cited2 interacts with LIM-homeobox gene 2 (Lhx2), Transcription factor AP2 (TFAP2), and nuclear receptors to function as a transcriptional co-activator. Cited2 is implicated in the control of cell growth and malignant transformation in Rat1 cells. Cited1 enhances Smad mediated transcription, suggesting that members of the Cited family may function as a co-activator in transforming growth factor-beta (TGF-beta) signaling. We have explored the function of Cited2 in the TGF-beta signaling pathway. In promoter reporter assays, Cited2 enhances Smad3 mediated transcription. This may occur through a direct physical association of Cited2 with Smads 2/3 and p300. We found that Cited2 modulates TGF-beta mediated upregulation of Matrix Metalloproteinase 9 (MMP9). In chromatin immunoprecipitation experiment, Cited2 and Smad3 are recruited to MMP9 promoter upon TGF-beta stimulation. Knockdown of Cited2 in MDA-MB-231 cells attenuates TGF-beta mediated cell migration, suggesting that Cited2 could play a role during tumor progression. Cited2 is downregulated by TGF-beta in MDA-MB-231 cells. We show that Smad2/3/4 and p38MAPK pathways are involved in TGF-beta mediated downregulation of Cited2. Nuclear run-on analysis and Cited2 promoter/reporter assays demonstrate that downregulation of Cited2 by TGF-beta is through posttranscriptional regulation. In transcriptional inhibitor assays, Cited2 mRNA turnover is increased under TGF-beta stimulation. We examined the expression of recombinant Cited2 gene introduced into MDA-MB-231 cells by stable transfection, and found that mRNA containing the Cited2 protein-coding region controlled by a heterologous promoter indeed responds to TGF-beta mediated downregulation. Our findings support that TGF-beta mediated downregulation of Cited2 is under posttranscriptional control, through Smad and p38MAPK pathways, and requires the presence of its coding sequence. The results of this thesis research provide supporting evidence of Cited2 as a transcription modulator in TGF-beta signaling and also suggest a feedback mechanism that downregulation of Cited2 by TGF-beta attenuates the expression of TGF-beta responsive genes such as MMP9 and MMP13. As MMP9 and MMP13 are highly involved in tumorigenesis, our research proposes that Cited2 could be a potential anticancer target. |
| Permanent Link: |
http://rave.ohiolink.edu/etdc/view?acc_num=case1147147222
http://hdl.handle.net/2374.OX/16793 |
| Date: | 2006 |
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