title: miR-17/20 sensitization of breast cancer cells to chemotherapy-induced apoptosis requires Akt1.
abstract: The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Herein, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse, demonstrates a requirement for Akt1 in miRNA-mediated cellular apoptosis. The miR-17/20 cluster is known to inhibit breast cancer cellular proliferation through G1/S cell cycle arrest via binding to the cyclin D1 3'UTR. Here we show that miR-17/20 overexpression sensitizes cells to apoptosis induced by either Doxorubicin or UV irradiation in MCF-7 cells via Akt1. miR-17/20 mediates apoptosis via increased p53 expression which promotes Akt degradation. Akt1⁻/⁻ mammary epithelial cells which express Akt2 and Akt3 demonstrated increased apoptosis to DNA damaging agents. Akt1 deficiency abolished the miR-17/20-mediated apoptosis. These results demonstrated a novel pathway through which miR17/20 regulate p53 and Akt controlling breast cancer cell apoptosis.
authors.affiliation: Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Zuoren
authors.initials: Z
authors.lastname: Yu
authors.forename: Zengguang
authors.initials: Z
authors.lastname: Xu
authors.forename: Gabriele
authors.initials: G
authors.lastname: Disante
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wright
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.forename: Ellen
authors.initials: E
authors.lastname: Gutman
authors.forename: Guangxue
authors.initials: G
authors.lastname: Wang
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.forename: Tieyan
authors.initials: T
authors.lastname: Li
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Xiang
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Xiongfei
authors.initials: X
authors.lastname: Yang
authors.forename: Xiaolai
authors.initials: X
authors.lastname: Yang
authors.forename: Richard
authors.initials: R
authors.lastname: Pestell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D004317:Doxorubicin; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt