Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3.
Myeloid leukemia factor 1 (MLF1) was first identified as the leukemic fusion protein NPM-MLF1 generated by the t(3;5)(q25.1;q34) chromosomal translocation. Although MLF1 expresses normally in a variety of tissues including hematopoietic stem cells and the overexpression of MLF1 correlates with malignant transformation in human cancer, little is known about how MLF1 is involved in the regulation of cell growth. Here we show that MLF1 is a negative regulator of cell cycle progression functioning upstream of the tumor suppressor p53. MLF1 induces p53-dependent cell cycle arrest in murine embryonic fibroblasts. This action requires a novel binding partner, subunit 3 of the COP9 signalosome (CSN3). A reduction in the level of CSN3 protein with small interfering RNA abrogated MLF1-induced G1 arrest and impaired the activation of p53 by genotoxic stress. Furthermore, ectopic MLF1 expression and CSN3 knockdown inversely affect the endogenous level of COP1, a ubiquitin ligase for p53. Exogenous expression of COP1 overcomes MLF1-induced growth arrest. These results indicate that MLF1 is a critical regulator of p53 and suggest its involvement in leukemogenesis through a novel CSN3-COP1 pathway.
Yoneda-Kato
Noriko
N
Department of Animal Molecular Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Takayama, Ikoma, Nara, Japan. noriko-k@bs.naist.jp
Tomoda
Kiichiro
K
Umehara
Mari
M
Arata
Yukinobu
Y
Kato
Jun-ya
JY
D000818:Animals; D000075686:COP9 Signalosome Complex; D019556:COS Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D007951:Leukemia, Myeloid / Q000209:etiology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C000618791:Cops3 protein, mouse; D004268:DNA-Binding Proteins; C100852:MLF1 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D000075686:COP9 Signalosome Complex