title: The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1.
abstract: RNF6 is a little-studied ring finger protein. In the present study, we found that RNF6 was overexpressed in various leukemia cells and that it accelerated leukemia cell proliferation, whereas knockdown of RNF6 delayed tumor growth in xenografts. To find out the mechanism of RNF6 overexpression in leukemia, we designed a series of truncated constructs of RNF6 regulatory regions in the luciferase reporter system. The results revealed that the region between -144 and -99 upstream of the RNF6 transcription start site was critical and that this region contained a PBX1 recognition element (PRE). PBX1 modulated RNF6 expression by binding to the specific PRE. When PRE was mutated, RNF6 transcription was completely abolished. Further studies showed that PBX1 collaborated with PREP1 but not MEIS1 to modulate RNF6 expression. Moreover, RNF6 expression could be suppressed by doxorubicin, a major anti-leukemia agent, via down-regulating PBX1. This study thus suggests that RNF6 overexpression in leukemia is under the direction of PBX1 and that the PBX1/RNF6 axis can be developed as a novel therapeutic target of leukemia.
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, the Asclepius Technology Company Group and Asclepius Cancer Research Center, Suzhou, Jiangsu 215123, China.
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.affiliation: the Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123.
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123.
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
authors.affiliation: the Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123.
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: the Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006.
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.affiliation: From the Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, the Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu 215123, and xinliangmao@suda.edu.cn.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C119753:RNF6 protein, human; C083400:PBX1 protein, human; D004317:Doxorubicin
keywords: RNF6; leukemia; oncogene; pre-B-cell leukemia homeobox 1; promoter modulation; ring finger protein; small interfering RNA (siRNA); transcription factor; tumor cell biology