title: PICT-1 triggers a pro-death autophagy through inhibiting rRNA transcription and AKT/mTOR/p70S6K signaling pathway.
abstract: PICT-1 was originally identified as a tumor suppressor. Here, we found that PICT-1 overexpression triggered pro-death autophagy without nucleolar disruption or p53 accumulation in U251 and MCF7 cells. Truncated PICT-1 fragments 181-346 and 1-346, which partly or totally lack nucleolar localization, showed weaker autophagy-inducing effects than full-length PICT-1 and a well-defined nucleolar mutant (181-479). Furthermore, PICT-1 partly localizes to the nucleolar fibrillar center (FC) and directly binds to ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF). Overexpression of PICT-1 or the 181-479 mutant, but not the 1-346 or 181-346 mutants, markedly inhibited the phosphorylation of UBF and the recruitment of rRNA polymerase I (Pol I) to the rDNA promoter in response to serum stimulation, thereby suppressing rRNA transcription, suggesting that rRNA transcription inhibition might be an important contributor to PICT-1-induced autophagy. This is supported by the finding that CX-5461, a specific Pol I inhibitor, also induced autophagy. In addition, both CX-5461 and PICT-1, but not the 1-346 or 181-346 mutants, significantly suppressed the activation of the Akt/mTOR/p70S6K signaling pathway. Our data show that PICT-1 triggers pro-death autophagy through inhibition of rRNA transcription and the inactivation of AKT/mTOR/p70S6K pathway, independent of nucleolar disruption and p53 activation.
authors.affiliation: The Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotechnology & Biomedicine, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Plant Cell Activities and Stress Adaptation, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Duo
authors.affiliation: Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou 511447, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology & Biomedicine, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology & Biomedicine, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Hsiangi
authors.initials: H
authors.lastname: Tsai
authors.affiliation: Department of Quality Inspection, Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Quality Inspection, Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China.
authors.forename: Lanzhen
authors.initials: L
authors.lastname: Zhou
authors.affiliation: The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology & Biomedicine, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Plant Cell Activities and Stress Adaptation, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Shenzhen Key Laboratory of Gene and Antibody Therapy, Center for Biotechnology & Biomedicine, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D001665:Binding Sites; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002466:Cell Nucleolus / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D009287:Naphthyridines / Q000494:pharmacology; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis* / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C557717:CX 5461; D004791:Enzyme Inhibitors; C500712:NOP53 protein, human; D009287:Naphthyridines; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D025521:Tumor Suppressor Proteins; C063844:transcription factor UBF; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D012318:RNA Polymerase I
keywords: PICT-1; autophagy; nucleolus; p53; rRNA transcription