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The PP2A-Aβ Gene is Regulated by Multiple Transcriptional Factors Including Ets-1, SP1/SP3, and RXRα /β

[ Vol. 12 , Issue. 8 ]

Author(s):

J. Liu, W. Ji, S. Sun, L. Zhang, H. -G. Chen, Y. Mao, L. Liu, X. Zhang, L. Gong, M. Deng, L. Chen, W. -J. Han, P. -C. Chen, W. -F. Hu, X. Hu, J. Liu, Z. Woodward, W. -B. Liu, Y. -M. Xiao, S. -P. Liang, Y. Liu, S. -J. Liu and D. W.-C. Li   Pages 982 - 994 ( 13 )

Abstract:


Protein phosphatase-2A (PP-2A) is a major serine/threonine phosphatase abundantly expressed in eukaryotes. PP-2A is a heterotrimer that contains a 65kD scaffold A subunit, a 36kD catalytic C subunit, and a regulatory B subunit of variable isoforms ranging from 54-130kDs. The scaffold subunits, PP2A-Aα/β, act as platforms for both the C and B subunits to bind, and thus are key structural components for PP-2A activity. Mutations in both genes encoding PP2A-Aα and PP2A-Aβ lead to carcinogenesis and likely other human diseases. Our previous work showed that the gene coding for PP2A-Aα is positively regulated by multiple transcription factors including Ets-1, CREB, and AP-2α but negatively regulated by SP-1/SP-3. In the present study, we have functionally dissected the promoter of the mouse PP2A-Aβ gene. Our results demonstrate that three major cis-elements, including the binding sites for Ets-1, SP1/SP3, and RXRα/β, are present in the proximal promoter of the mouse PP2A-Aβ gene. Gel mobility shifting assays reveal that Ets-1, SP1/SP3, and RXRα/β all bind to PP2A-Aβ gene promoter. In vitro mutagenesis and reporter gene activity assays demonstrate that while Ets-1 displays negative regulation, SP1/SP3 and RXRα/β positively regulate the promoter of the PP2A-Aβ gene. Co-expression of the cDNAs encoding Ets-1, SP1/SP3, or RXRα/β and the luciferase reporter gene driven by PP2A-Aβ promoter further confirm their control over the PP2A-Aβ promoter. Finally, ChIP assays demonstrate that Ets-1, SP1/SP3, and RXRα/β can all bind to the PP2A-Aβ gene promoter. Together, our results reveal that multiple transcription factors regulate the PP2A-Aβ gene. Moreover, our results provide important information explaining why PP2A-Aα and PP2A-Aβ display distinct expression levels.

Keywords:

Protein phosphorylation, dephosphorylation, PP-2A, PP2A-Aβ, gene regulation, Ets, SP1, SP3, RXRα/β, lens, retina, cataract, cancer, eukaryotic cells, cell transformation.

Affiliation:

Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.



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