UBTOR/KIAA1024 regulates neurite outgrowth and neoplasia through mTOR signaling

Hefei Zhang; Quan Zhang; Ge Gao; Xinjian Wang; Tiantian Wang; Zhitao Kong; Guoxiang Wang; Cuizhen Zhang; Yun Wang; Gang Peng

doi:10.1371/journal.pgen.1007583

UBTOR/KIAA1024 regulates neurite outgrowth and neoplasia through mTOR signaling

PLoS Genet. 2018 Aug 6;14(8):e1007583. doi: 10.1371/journal.pgen.1007583. eCollection 2018 Aug.

Authors

Affiliation

¹ Institute of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.

Abstract

The mTOR signaling pathways regulate cell growth and are involved in multiple human diseases. Here, we identify UBTOR, a previously unannotated gene as a functional player in regulating cell growth and mTOR signaling. Reduction of UBTOR function in cultured hippocampal neurons and PC12 cells promotes neurite outgrowth. UBTOR depletion activates mTOR signaling and promotes cell growth, whilst UBTOR overexpression suppresses colony formation in cancer cell lines. Studies in cultured cells and zebrafish model show that UBTOR inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, and ubtor gene disruption result in higher mTOR activity and aggravate HRAS(G12V) induced neoplasia in the zebrafish. Lastly, UBTOR depletion promotes tumor growth and mTOR signaling in a xenograft mouse model. Together, our results demonstrate how UBTOR regulates cell growth and neoplasia via mTOR signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / genetics*
Chromosome Mapping
Female
Gene Deletion
Gene Expression Regulation*
HEK293 Cells
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Neuronal Outgrowth / genetics*
PC12 Cells
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Rats
Rats, Sprague-Dawley
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*
Signal Transduction
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Xenograft Model Antitumor Assays
Zebrafish / genetics
Zebrafish / metabolism

Substances

MINAR1 protein, human
RNA, Small Interfering
Receptors, Cell Surface
TOR Serine-Threonine Kinases

Grants and funding

This work was supported by the National Natural Science Foundation of China (URL:http://www.nsfc.gov.cn/) (31171074, 31371099 and 31571067 to GP), the Pujiang Talent Project (URL:http://www.stcsm.gov.cn)(09PJ1401900 to GP), and the Shanghai Science and Technology Committee (URL:http://www.stcsm.gov.cn) (15ZR1402300 to GP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.