p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins.
The tumor suppressor p53 is a central regulator of cell-cycle arrest and apoptosis by acting as a transcription factor to regulate numerous genes. We identified all human p53-regulated mRNAs by microarray analyses and searched for protein-coding genes which contain intronic miRNAs. Among others, this analysis yielded the panthothenate kinase 1 (PANK1) gene and its intronic miRNA-107. We showed that miRNA-107 and PANK1 are coregulated by p53 in different cell systems. The PANK1 protein, which catalyzes the rate-limiting step of coenzyme A biosynthesis, is also upregulated by p53. We observed that p53 directly activates PANK1 and miRNA-107 transcription through a binding site in the PANK1 promoter. Furthermore, p53 is recruited to the PANK1 promoter after DNA damage. In order to get more insight into miRNA-107 function we investigated its potential target genes. Cell-cycle regulators are significantly enriched among predicted miRNA-107 targets. We found miRNA-107-dependent regulation of two important regulators of G(1)/S progression, CDK6 and the RB-related 2 gene RBL2 (p130). CDK6 and p130 proteins are downregulated upon miRNA-107 expression. Our results uncover a novel miRNA-dependent signaling pathway which leads to downregulation of cell cycle proteins in the absence of transcriptional repression.
Böhlig
Levin
L
Department of Obstetrics and Gynecology, University of Leipzig, Leipzig, Germany.
Friedrich
Maik
M
Engeland
Kurt
K
D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D019295:Computational Biology; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006801:Humans; D007438:Introns; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; C549045:MIRN107 microRNA, human; D035683:MicroRNAs; D050717:Retinoblastoma-Like Protein p130; D016159:Tumor Suppressor Protein p53; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D051361:Cyclin-Dependent Kinase 6