Abrogation of the transactivation activity of p53 by BCCIP down-regulation.
The tumor suppression function of p53 is mostly conferred by its transactivation activity, which is inactivated by p53 mutations in approximately 50% of human cancers. In cancers harboring wild type p53, the p53 transactivation activity may be compromised by other mechanisms. Identifying the mechanisms by which wild type p53 transactivation activity can be abrogated may provide insights into the molecular etiology of cancers harboring wild type p53. In this report, we show that BCCIP, a BRCA2 and CDKN1A-interacting protein, is required for the transactivation activity of wild type p53. In p53 wild type cells, BCCIP knock down by RNA interference diminishes the transactivation activity of p53 without reducing the p53 protein level, inhibits the binding of p53 to the promoters of p53 target genes p21 and HDM2, and reduces the tetrameric formation of p53. These data demonstrate a critical role of BCCIP in maintaining the transactivation activity of wild type p53 and further suggest down-regulation of BCCIP as a novel mechanism to impair the p53 function in cells harboring wild type p53.
Meng
Xiangbing
X
Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA.
Yue
Jingyin
J
Liu
Zhihe
Z
Shen
Zhiyuan
Z
D000818:Animals; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
C415366:BCCIP protein, human; C493956:CDKN1A protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2