PMID- 31609760
OWN - NLM
STAT- MEDLINE
DCOM- 20200915
LR  - 20200915
IS  - 1473-5741 (Electronic)
IS  - 0959-4973 (Linking)
VI  - 30
IP  - 10
DP  - 2019 Nov
TI  - The signaling axis of Rac1-TFEB regulates autophagy and tumorigenesis.
PG  - 1031-1037
LID - 10.1097/CAD.0000000000000816 [doi]
AB  - Macroautophagy (hereafter referred to as autophagy) plays essential roles in 
      cellular and organismal homeostasis. Transcription factor EB (TFEB) is a master 
      regulator of autophagy and lysosome biogenesis. It is not fully understood how 
      the function of TFEB in autophagy pathway is regulated. Here, we show that Rac1 
      GTPase is a negative modulator of autophagy by targeting TFEB. Mechanistically, 
      Rac1 reduces autophagy flux by repressing the expressing of autophagy genes. 
      Further investigation revealed that under nutrient-rich conditions, mammalian 
      target of rapamycin (mTOR) phosphorylates TFEB to facilitate the interaction 
      between Rac1 and TFEB. Biochemical dissection uncovered that guanosine 
      5'-triphosphate (GTP)-bound form of Rac1 selectively interacts with 
      phosphorylated TFEB. This inhibitory interaction prevents the dephosphorylation 
      and nucleus translocation of TFEB, which hampers the transcriptional activation 
      of autophagy-related genes. Furthermore, Rac1-TFEB axis appeared to be important 
      for tumorigenesis, as overexpression of dephosphorylated mutant of TFEB was able 
      to delay the tumor growth driven by Rac1 overexpression. Together, this study not 
      only elucidates a previously uncharacterized autophagy regulation mechanism 
      involving Rac1 and TFEB under physiological and pathological conditions but also 
      suggests a strategy to treat cancers that are driven by Rac1 overexpression.
FAU - Ma, Lijie
AU  - Ma L
AD  - Department of Pharmacology, Basic Medical College.
FAU - Ma, Yuehong
AU  - Ma Y
AD  - Department of Pharmacology, Basic Medical College.
FAU - Zhang, Ziying
AU  - Zhang Z
AD  - Department of Pharmacology, Basic Medical College.
FAU - Wang, Qi
AU  - Wang Q
AD  - Emergency Department, Affiliated Hospital, Inner Mongolia Medical University, 
      Hohhot, Inner Mongolia, China.
FAU - Liu, Xudong
AU  - Liu X
AD  - Emergency Department, Affiliated Hospital, Inner Mongolia Medical University, 
      Hohhot, Inner Mongolia, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Anticancer Drugs
JT  - Anti-cancer drugs
JID - 9100823
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (RAC1 protein, human)
RN  - 0 (TFEB protein, human)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - Autophagy/genetics/*physiology
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/*metabolism
MH  - Carcinogenesis
MH  - Gene Expression Regulation
MH  - Guanosine Triphosphate/metabolism
MH  - HeLa Cells
MH  - Hep G2 Cells
MH  - Humans
MH  - Mice, SCID
MH  - Signal Transduction
MH  - Xenograft Model Antitumor Assays
MH  - rac1 GTP-Binding Protein/genetics/*metabolism
EDAT- 2019/10/15 06:00
MHDA- 2020/09/17 06:00
CRDT- 2019/10/15 06:00
PHST- 2019/10/15 06:00 [pubmed]
PHST- 2020/09/17 06:00 [medline]
PHST- 2019/10/15 06:00 [entrez]
AID - 10.1097/CAD.0000000000000816 [doi]
PST - ppublish
SO  - Anticancer Drugs. 2019 Nov;30(10):1031-1037. doi: 10.1097/CAD.0000000000000816.