RGD Reference Report - Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2. - Rat Genome Database

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Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2.

Authors: Li, W  Petrimpol, M  Molle, KD  Hall, MN  Battegay, EJ  Humar, R 
Citation: Li W, etal., Circ Res. 2007 Jan 5;100(1):79-87. Epub 2006 Nov 16.
RGD ID: 2307383
Pubmed: PMID:17110594   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000253094.03023.3f   (Journal Full-text)

A central regulator of cell growth that has been implicated in responses to stress such as hypoxia is mTOR (mammalian Target Of Rapamycin). We have shown previously that mTOR is required for angiogenesis in vitro and endothelial cell proliferation in response to hypoxia. Here we have investigated mTOR-associated signaling components under hypoxia and their effects on cell proliferation in rat aortic endothelial cells (RAECs). Hypoxia (1% O(2)) rapidly (>30 minutes) and in a concentration-dependent manner promoted rapamycin-sensitive and sustained phosphorylation of mTOR-Ser2448 followed by nuclear translocation in RAECs. Similarly, hypoxia induced phosphorylation of the mTORC2 substrate Akt-Ser473 (3 to 6 hours at 1% O(2)) and a brief phosphorylation peak of the mTORC1 substrate S6 kinase-Thr389 (10 to 60 minutes). Phosphorylation of Akt was inhibited by mTOR knockdown and partially with rapamycin. mTOR knockdown, rapamycin, or Akt inhibition specifically and significantly inhibited proliferation of serum-starved RAECs under hypoxia (P<0.05; n> or =4). Similarly, hypoxia induced Akt-dependent and rapamycin-sensitive proliferation in mouse embryonic fibroblasts. This response was partially blunted by hypoxia-inducible factor-1alpha knockdown and not affected by TSC2 knockout. Finally, mTORC2 inhibition by rictor silencing, especially (P<0.001; n=7), and mTORC1 inhibition by raptor silencing, partially (P<0.05; n=7), inhibited hypoxia-induced RAEC proliferation. Thus, mTOR mediates an early response to hypoxia via mTORC1 followed by mTORC2, promoting endothelial proliferation mainly via Akt signaling. mTORC1 and especially mTORC2 might therefore play important roles in diseases associated with hypoxia and altered angiogenesis.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MtorRatTORC1 complex  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MtorRatprotein serine/threonine kinase activity  IMP  RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Objects Annotated

Genes (Rattus norvegicus)
Mtor  (mechanistic target of rapamycin kinase)
Rictor  (RPTOR independent companion of MTOR, complex 2)
Rptor  (regulatory associated protein of MTOR, complex 1)

Genes (Mus musculus)
Mtor  (mechanistic target of rapamycin kinase)
Rictor  (RPTOR independent companion of MTOR, complex 2)
Rptor  (regulatory associated protein of MTOR, complex 1)

Genes (Homo sapiens)
MTOR  (mechanistic target of rapamycin kinase)
RICTOR  (RPTOR independent companion of MTOR complex 2)
RPTOR  (regulatory associated protein of MTOR complex 1)


Additional Information