PMID- 18697743
OWN - NLM
STAT- MEDLINE
DCOM- 20081125
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 42
DP  - 2008 Oct 17
TI  - Stress and IGF-I differentially control cell fate through mammalian target of 
      rapamycin (mTOR) and retinoblastoma protein (pRB).
PG  - 28265-73
LID - 10.1074/jbc.M805724200 [doi]
AB  - Significant discoveries have recently contributed to our knowledge of 
      intracellular growth factor and nutrient signaling via mTOR (mammalian target of 
      rapamycin). This signaling pathway is essential in cellular metabolism and cell 
      survival by enhancing protein translation through phosphorylation of 4EBP-1 and 
      p70S6K. Growth factors like insulin-like growth factor-I induce mTOR to prevent 
      cell death during cellular stress. Agents targeting mTOR are of major interest as 
      anticancer agents. We show here, using human breast cancer cells, that certain 
      types of stress activate mTOR leading to 4E-BP1 and p70S6K phosphorylation. UV 
      treatment increased phosphorylation of the translation inhibitor eIF2alpha, 
      suggesting a potential mechanism for UV activation of Akt and mTOR. c-Myc, a 
      survival protein regulated by cap-dependent protein translation, increased with 
      IGF-I treatment, but this response was not inhibited by rapamycin. Additionally, 
      UV treatment potently increased c-Myc degradation, which was reduced by 
      co-treatment with the proteasomal inhibitor, MG-132. Together, these data suggest 
      that protein translation does not strongly mediate cell survival in these models. 
      In contrast, the phosphorylation status of retinoblastoma protein (pRB) was 
      mediated by mTOR through its inhibitory effects on phosphatase activity. This 
      effect was most notable during DNA damage and rapamycin treatment. 
      Hypophosphorylated pRB was susceptible to inactivation by caspase-mediated 
      cleavage, resulting in cell death. Reduction of pRB expression inhibited IGF-I 
      survival effects. Our data support an important role of phosphatases and pRB in 
      IGF-I/mTOR-mediated cell survival. These studies provide new directions in 
      optimizing anticancer efficacy of mTOR inhibitors when used in combination with 
      DNA-damaging agents.
FAU - Popowski, Melissa
AU  - Popowski M
AD  - College of Pharmacy, University of Texas, Austin, Texas 78712-0125, USA.
FAU - Ferguson, Heather A
AU  - Ferguson HA
FAU - Sion, Amy M
AU  - Sion AM
FAU - Koller, Erich
AU  - Koller E
FAU - Knudsen, Erik
AU  - Knudsen E
FAU - Van Den Berg, Carla L
AU  - Van Den Berg CL
LA  - eng
GR  - CA 89288/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20080811
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Leupeptins)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Retinoblastoma Protein)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Enzyme Inhibitors/pharmacology
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - Humans
MH  - Insulin-Like Growth Factor I/*metabolism
MH  - Leupeptins/pharmacology
MH  - Models, Biological
MH  - Phosphorylation
MH  - Proteasome Inhibitors
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-myc/metabolism
MH  - Retinoblastoma Protein/*metabolism
MH  - Stress, Physiological
MH  - TOR Serine-Threonine Kinases
MH  - Ultraviolet Rays
PMC - PMC2568931
EDAT- 2008/08/14 09:00
MHDA- 2008/12/17 09:00
PMCR- 2009/10/17
CRDT- 2008/08/14 09:00
PHST- 2008/08/14 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/08/14 09:00 [entrez]
PHST- 2009/10/17 00:00 [pmc-release]
AID - S0021-9258(20)64222-3 [pii]
AID - 28265 [pii]
AID - 10.1074/jbc.M805724200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Oct 17;283(42):28265-73. doi: 10.1074/jbc.M805724200. Epub 2008 
      Aug 11.