Oncotarget

Research Papers:

PICT-1 triggers a pro-death autophagy through inhibiting rRNA transcription and AKT/mTOR/p70S6K signaling pathway

Hongbo Chen, Yanhong Duo, Bo Hu, Zhiwei Wang, Fang Zhang, Hsiangi Tsai, Jianping Zhang, Lanzhen Zhou, Lijun Wang, Xinyu Wang _ and Laiqiang Huang

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Oncotarget. 2016; 7:78747-78763. https://doi.org/10.18632/oncotarget.12288

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Abstract

Hongbo Chen1,2,*, Yanhong Duo3,*, Bo Hu4, Zhiwei Wang5, Fang Zhang1, Hsiangi Tsai1,2, Jianping Zhang6, Lanzhen Zhou6, Lijun Wang1, Xinyu Wang3, Laiqiang Huang1,2

1The 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

2School of Life Sciences, Tsinghua University, Beijing 100084, China

3Key Laboratory of Plant Cell Activities and Stress Adaptation, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou 730000, China

4Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China

5Department of Laboratory Medicine, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou 511447, China

6Department of Quality Inspection, Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China

*These authors have contributed equally to this work

Correspondence to:

Hongbo Chen, email: chen.hongbo@sz.tsinghua.edu.cn

Xinyu Wang, email: wangxy@lzu.edu.cn

Laiqiang Huang, email: huanglq@tsinghua.edu.cn

Keywords: PICT-1, nucleolus, autophagy, rRNA transcription, p53

Received: May 26, 2016    Accepted: September 16, 2016    Published: September 27, 2016

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.


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