Identification of TopBP1 as a c-Abl-interacting protein and a repressor for c-Abl expression.
Expression of BCR-ABL is the leading cause of chronic myelogenous leukemia. In chronic myelogenous leukemia cells, c-Abl expression is silenced by promoter methylation. In addition, the level of c-Abl needs to be tightly and constantly regulated due to its cytotoxicity and its rapid degradation after activation. Yet the regulation of c-Abl expression remains unclear. In an effort to gain better understanding of c-Abl function, we performed a glutathione S-transferase-Abl pull-down screen and identified TopBP1, a topoisomerase IIbeta-binding protein that contains Brca1 C-terminal motifs and has been implicated in DNA damage response. Their physical interaction was verified by in vitro and in vivo assays with TopBP1 found as a substrate of Abl proteins. TopBP1 could repress the expression of c-Abl at both mRNA and protein levels. Reporter assays indicate that TopBP1 directly repressed the promoter activity of c-Abl. Furthermore, TopBP1 repressed expression of c-Abl through a novel mechanism that involved histone deacetylation and DNA methylation. This transcriptional repression was inhibited by c-Abl in a kinase-dependent manner. The dual antagonistic interplay between c-Abl and TopBP1 may also provide a mechanism for fine-tuning of c-Abl levels.
Zeng
Li
L
Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673.
Hu
Yuanyu
Y
Li
Baojie
B
D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C110513:TOPBP1 protein, human; D005982:Glutathione Transferase; D016315:Proto-Oncogene Proteins c-abl