Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation.
Chronic lymphocytic leukemia (CLL) is characterized by cells that exhibit dysfunctional apoptosis. Here, we show that deacetylase inhibition led to the E2F1- and myc-mediated transcriptional activation of the microRNA miR106b in primary CLL cells. Induction of miR106b was associated with a down-regulation in the levels of the E3-ubiquitin ligase Itch. Decreases in Itch protein levels were associated with a reciprocal accumulation of its proapoptotic substrate, TAp73 (p73), and induction of p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein. This event was accompanied by mitochondrial dysfunction, processing of caspase-9, and apoptosis of CLL cells. Ectopic expression of miR106b in CLL cells demonstrated that Itch was a direct target of miR106b such that miR106b-induced decreases in Itch resulted in an accumulation of p73. Thus, our results identify a novel regulatory mechanism wherein microRNA regulate cell survival by mediating the posttranscriptional down-regulation of an ubiquitin ligase, leading to the induction of a proapoptotic regulator in malignant cells. Silencing of miRNA expression in CLL may selectively suppress proapoptotic pathways, providing such tumors with a survival advantage. Consequently, chemotherapeutic drugs that activate miR106b could initiate a p53-independent mechanism that targets CLL cells.
Sampath
Deepa
D
Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. dsampath@mdanderson.org
Calin
George A
GA
Puduvalli
Vinay K
VK
Gopisetty
Gopal
G
Taccioli
Cristian
C
Liu
Chang-Gong
CG
Ewald
Brett
B
Liu
Chaomei
C
Keating
Michael J
MJ
Plunkett
William
W
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D004268:DNA-Binding Proteins; C542541:MIRN106 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C506433:CASP9 protein, human; D053453:Caspase 9