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TPT1 (tumor protein, translationally-controlled 1) negatively regulates autophagy through the BECN1 interactome and an MTORC1-mediated pathway

Title
TPT1 (tumor protein, translationally-controlled 1) negatively regulates autophagy through the BECN1 interactome and an MTORC1-mediated pathway
Authors
Bae, Seong-YeonByun, SanguineBae, Soo HanMin, Do SikWoo, Hyun AeLee, Kyunglim
Ewha Authors
이경림우현애
SCOPUS Author ID
이경림scopus; 우현애scopus
Issue Date
2017
Journal Title
AUTOPHAGY
ISSN
1554-8627JCR Link1554-8635JCR Link
Citation
vol. 13, no. 5, pp. 820 - 833
Keywords
autophagyBCL2BECN1MTORC1TP53 target geneTPT1/TCTP
Publisher
TAYLOR & FRANCIS INC
Indexed
SCIE; SCOPUS WOS scopus
Abstract
TPT1/TCTP (tumor protein, translationally-controlled 1) is highly expressed in tumor cells, known to participate in various cellular activities including protein synthesis, growth and cell survival. In addition, TPT1 was identified as a direct target of the tumor suppressor TP53/p53 although little is known about the mechanism underlying the anti-survival function of TPT1. Here, we describe a role of TPT1 in the regulation of the MTORC1 pathway through modulating the molecular machinery of macroautophagy/autophagy. TPT1 inhibition induced cellular autophagy via the MTORC1 and AMPK pathways, which are inhibited and activated, respectively, during treatment with the MTOR inhibitor rapamycin. We also found that the depletion of TPT1 potentiated rapamycin-induced autophagy by synergizing with MTORC1 inhibition. We further demonstrated that TPT1 knockdown altered the BECN1 interactome, a representative MTOR-independent pathway, to stimulate autophagosome formation, via downregulating BCL2 expression through activating MAPK8/JNK1, and thereby enhancing BECN1-phosphatidylinositol 3-kinase (PtdIns3K)-UVRAG complex formation. Furthermore, reduced TPT1 promoted autophagic flux by modulating not only early steps of autophagy but also autophagosome maturation. Consistent with in vitro findings, in vivo organ analysis using Tpt1 heterozygote knockout mice showed that autophagy is enhanced because of haploinsufficient TPT1 expression. Overall, our study demonstrated the novel role of TPT1 as a negative regulator of autophagy that may have potential use in manipulating various diseases associated with autophagic dysfunction.
DOI
10.1080/15548627.2017.1287650
Appears in Collections:
약학대학 > 약학과 > Journal papers
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