PMID- 25557637
OWN - NLM
STAT- MEDLINE
DCOM- 20151201
LR  - 20211203
IS  - 1873-4286 (Electronic)
IS  - 1381-6128 (Linking)
VI  - 21
IP  - 12
DP  - 2015
TI  - Evaluation of the in vivo safety profiles of Rictor inhibition using a zebrafish 
      model.
PG  - 1645-53
AB  - The mammalian target of rapamycin (mTOR), which assembles into two distinct 
      multiprotein complexes, called mTORC1 and mTORC2, is known as a central regulator 
      of cellular proliferation and maturation. Rictor is one of the key components of 
      mTORC2 and acts as a scaffolding protein to maintain and stabilize mTORC2. 
      Currently, mTORC2 and/or Rictor are increasingly being recognized as attractive 
      targets for novel modalities of anti-cancer therapy. Unfortunately, the safety 
      profile of Rictor- or mTORC2-targeting strategies has been poorly understood due 
      to the lack of an ideal animal model. In the present study, we used zebrafish as 
      an in vivo model system to evaluate the safety of Rictor inhibition. Our data 
      showed that the Rictor of zebrafish was identified to have high sequence homology 
      with mouse Rictor and human Rictor, which validates the rationale of using 
      zebrafish as a research model. Rictor was dispensable in neonatal hematopoiesis 
      and angiogenesis and was not required for vasculogenesis and other organs. These 
      data are consistent with those of previous observations of using tissue-specific 
      Rictor knockout mice model and have potentially important clinical implications. 
      Our findings highlight a good in vivo safety profile for Rictor- or 
      mTORC2-targeting therapy and point to the feasibility and advantages of using the 
      zebrafish model to evaluate the safety of the therapeutic target.
FAU - Cao, Yang
AU  - Cao Y
FAU - Jiang, Lijun
AU  - Jiang L
FAU - Zhao, Lei
AU  - Zhao L
FAU - Zhou, Xiaoxi
AU  - Zhou X
FAU - Wang, Na
AU  - Wang N
FAU - Zhang, Peilin
AU  - Zhang P
FAU - Tang, Yuting
AU  - Tang Y
FAU - Zhou, Jianfeng
AU  - Zhou J
AD  - Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, Hubei, 430030, P.R. China. 
      jfzhou@tjh.tjmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
PL  - United Arab Emirates
TA  - Curr Pharm Des
JT  - Current pharmaceutical design
JID - 9602487
RN  - 0 (Carrier Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (RICTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Zebrafish Proteins)
RN  - 0 (rictor protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/*genetics
MH  - Feasibility Studies
MH  - *Gene Knockdown Techniques
MH  - Hematopoiesis/physiology
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Models, Animal
MH  - Multiprotein Complexes/*genetics
MH  - Neovascularization, Physiologic/physiology
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Sequence Analysis, DNA
MH  - Species Specificity
MH  - TOR Serine-Threonine Kinases/*genetics
MH  - *Zebrafish
MH  - Zebrafish Proteins/*genetics
EDAT- 2015/01/06 06:00
MHDA- 2015/12/15 06:00
CRDT- 2015/01/06 06:00
PHST- 2014/10/06 00:00 [received]
PHST- 2014/12/31 00:00 [accepted]
PHST- 2015/01/06 06:00 [entrez]
PHST- 2015/01/06 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - CPD-EPUB-64332 [pii]
AID - 10.2174/1381612821666150105120955 [doi]
PST - ppublish
SO  - Curr Pharm Des. 2015;21(12):1645-53. doi: 10.2174/1381612821666150105120955.