PMID- 15775987
OWN - NLM
STAT- MEDLINE
DCOM- 20050607
LR  - 20211203
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 24
IP  - 6
DP  - 2005 Mar 23
TI  - Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway 
      for viral replication.
PG  - 1211-21
AB  - Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple 
      cellular replication from the many intra- and extracellular factors that normally 
      control it. Here we show that adenovirus encodes two proteins that activate the 
      mammalian target of rapamycin (mTOR) for viral replication, even under 
      nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor 
      signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and 
      mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not 
      affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates 
      mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a 
      mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. 
      We also show that mTOR activation is required for efficient S-phase entry, 
      independently of E2F activation, in adenovirus-infected quiescent primary cells. 
      These data reveal that adenovirus has evolved proteins that activate the mTOR 
      pathway, irrespective of the cellular microenvironment, and which play a 
      requisite role in viral replication.
FAU - O'Shea, Clodagh
AU  - O'Shea C
AD  - Cancer Research Institute, University of California, San Francisco, CA, USA. 
      oshea@cc.ucsf.edu
FAU - Klupsch, Kristina
AU  - Klupsch K
FAU - Choi, Serah
AU  - Choi S
FAU - Bagus, Bridget
AU  - Bagus B
FAU - Soria, Conrado
AU  - Soria C
FAU - Shen, Jerry
AU  - Shen J
FAU - McCormick, Frank
AU  - McCormick F
FAU - Stokoe, David
AU  - Stokoe D
LA  - eng
GR  - R01CA79548/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050303
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (Adenovirus E4 Proteins)
RN  - 0 (Neuropeptides)
RN  - 0 (PPP2R1B protein, human)
RN  - 0 (Ppp2r1b protein, mouse)
RN  - 0 (RHEB protein, human)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Adenoviridae/*physiology
MH  - Adenovirus E4 Proteins/genetics/*metabolism
MH  - Cell Line
MH  - DNA Replication/physiology
MH  - Enzyme Activation
MH  - Humans
MH  - Monomeric GTP-Binding Proteins/metabolism
MH  - Mutation/genetics
MH  - Neuropeptides/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoprotein Phosphatases/analysis/metabolism
MH  - Phosphorylation
MH  - Protein Biosynthesis
MH  - Protein Kinases/*metabolism
MH  - Protein Phosphatase 2
MH  - Ras Homolog Enriched in Brain Protein
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - S Phase/physiology
MH  - TOR Serine-Threonine Kinases
MH  - Virus Replication/*physiology
PMC - PMC556401
EDAT- 2005/03/19 09:00
MHDA- 2005/06/09 09:00
PMCR- 2005/03/23
CRDT- 2005/03/19 09:00
PHST- 2004/12/10 00:00 [received]
PHST- 2005/02/03 00:00 [accepted]
PHST- 2005/03/19 09:00 [pubmed]
PHST- 2005/06/09 09:00 [medline]
PHST- 2005/03/19 09:00 [entrez]
PHST- 2005/03/23 00:00 [pmc-release]
AID - 7600597 [pii]
AID - 10.1038/sj.emboj.7600597 [doi]
PST - ppublish
SO  - EMBO J. 2005 Mar 23;24(6):1211-21. doi: 10.1038/sj.emboj.7600597. Epub 2005 Mar 
      3.