Transcriptional regulation of PP2A-A alpha is mediated by multiple factors including AP-2alpha, CREB, ETS-1, and SP-1.
Protein phosphatases-2A (PP-2A) is a major serine/threonine phosphatase and accounts for more than 50% serine/threonine phosphatase activity in eukaryotes. The holoenzyme of PP-2A consists of the scaffold A subunit, the catalytic C subunit and the regulatory B subunit. The scaffold subunits, PP2A-A alpha/beta, provide a platform for both C and B subunits to bind, thus playing a crucial role in providing specific PP-2A activity. Mutation of the two genes encoding PP2A-A alpha/beta leads to carcinogenesis and likely other human diseases. Regulation of these genes by various factors, both extracellular and intracellular, remains largely unknown. In the present study, we have conducted functional dissection of the promoter of the mouse PP2A-A alpha gene. Our results demonstrate that the proximal promoter of the mouse PP2A-A alpha gene contains numerous cis-elements for the binding of CREB, ETS-1, AP-2 alpha, SP-1 besides the putative TFIIB binding site (BRE) and the downstream promoter element (DPE). Gel mobility shifting assays revealed that CREB, ETS-1, AP-2 alpha, and SP-1 all bind to PP2A-A alpha gene promoter. In vitro mutagenesis and reporter gene activity assays reveal that while SP-1 displays negative regulation, CREB, ETS-1 and AP-2A alpha all positively regulate the promoter of the PP2A-A alpha gene. ChIP assays further confirm that all the above transcription factors participate the regulation of PP2A-A alpha gene promoter. Together, our results reveal that multiple transcription factors regulate the PP2A-A alpha gene.
Chen
He-Ge
HG
Department of Biochemistry & Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Han
Wen-Jun
WJ
Deng
Mi
M
Qin
Jichao
J
Yuan
Dan
D
Liu
Jin-Ping
JP
Xiao
Ling
L
Gong
Lili
L
Liang
Songping
S
Zhang
Jian
J
Liu
Yun
Y
Li
David Wan-Cheng
DW
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D050784:Proto-Oncogene Protein c-ets-1; D016329:Sp1 Transcription Factor; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D054648:Protein Phosphatase 2