2. Academic Validation
  3. PICT-1 triggers a pro-death autophagy through inhibiting rRNA transcription and AKT/mTOR/p70S6K signaling pathway

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

  • Oncotarget. 2016 Nov 29;7(48):78747-78763. doi: 10.18632/oncotarget.12288.
Hongbo Chen 1 2,  Yanhong Duo 3,  Bo Hu 4,  Zhiwei Wang 5,  Fang Zhang 6,  Hsiangi Tsai 6 2,  Jianping Zhang 7,  Lanzhen Zhou 7,  Lijun Wang 6,  Xinyu Wang 3,  Laiqiang Huang 6 2
Affiliations

Affiliations

  • 1 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.
  • 2 School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Key Laboratory of Plant Cell Activities and Stress Adaptation, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
  • 4 Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 5 Department of Laboratory Medicine, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou 511447, China.
  • 6 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.
  • 7 Department of Quality Inspection, Shenzhen Weiguang Biological Products Co., Ltd, Shenzhen 518107, China.
PMID: 27729611 DOI: 10.18632/oncotarget.12288
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.

Keywords

PICT-1; autophagy; nucleolus; p53; rRNA transcription.

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