p53 Transactivates the phosphatase MKP1 through both intronic and exonic p53 responsive elements.
The tumor suppressor p53 protein can negatively regulate mitogen-activated protein kinase (MAPK) signaling via the induction of MAPK phosphatases. We have recently described that MKP1, a member of the MAPK phosphatase family, is transcriptionally regulated by p53 via a p53 responsive element located in the second intron of the MKP1 gene. Here, we identify an additional p53 responsive element located in the third exon of the MKP1 gene. We demonstrated in reporter gene assays that p53 binds to this exonic element and transactivates MKP1. Furthermore, we showed that this exonic responsive element could be bound by p53 both in vitro and in vivo as demonstrated by gel shift and ChIP assays, respectively. Mutation of either exonic or intronic site resulted in a ~50% decrease in luciferase reporter activity, and loss of both sites completely abrogated p53-dependent transcription of MKP1. These results suggest that each element sufficiently confers p53 responsiveness and that both elements are required for its full activation. Thus, our results provide the mechanism by which p53 controls transcription of the MKP1 gene.
Yang
Huanjie
H
Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Wu
Gen Sheng
GS
D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D024202:Electrophoretic Mobility Shift Assay; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D007438:Introns / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D016159:Tumor Suppressor Protein p53; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases