PMID- 21454539
OWN - NLM
STAT- MEDLINE
DCOM- 20110701
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 18
DP  - 2011 May 6
TI  - Phosphomimetic substitution of heterogeneous nuclear ribonucleoprotein A1 at 
      serine 199 abolishes AKT-dependent internal ribosome entry site-transacting 
      factor (ITAF) function via effects on strand annealing and results in mammalian 
      target of rapamycin complex 1 (mTORC1) inhibitor sensitivity.
PG  - 16402-13
LID - 10.1074/jbc.M110.205096 [doi]
AB  - The relative activity of the AKT kinase has been demonstrated to be a major 
      determinant of sensitivity of tumor cells to mammalian target of rapamycin (mTOR) 
      complex 1 inhibitors. Our previous studies have shown that the multifunctional 
      RNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) A1 regulates 
      a salvage pathway facilitating internal ribosome entry site (IRES)-dependent mRNA 
      translation of critical cellular determinants in an AKT-dependent manner 
      following mTOR inhibitor exposure. This pathway functions by stimulating 
      IRES-dependent translation in cells with relatively quiescent AKT, resulting in 
      resistance to rapamycin. However, the pathway is repressed in cells with elevated 
      AKT activity, rendering them sensitive to rapamycin-induced G(1) arrest as a 
      result of the inhibition of global eIF-4E-mediated translation. AKT 
      phosphorylation of hnRNP A1 at serine 199 has been demonstrated to inhibit 
      IRES-mediated translation initiation. Here we describe a phosphomimetic mutant of 
      hnRNP A1 (S199E) that is capable of binding both the cyclin D1 and c-MYC IRES 
      RNAs in vitro but lacks nucleic acid annealing activity, resulting in inhibition 
      of IRES function in dicistronic mRNA reporter assays. Utilizing cells in which 
      AKT is conditionally active, we demonstrate that overexpression of this mutant 
      renders quiescent AKT-containing cells sensitive to rapamycin in vitro and in 
      xenografts. We also demonstrate that activated AKT is strongly correlated with 
      elevated Ser(P)(199)-hnRNP A1 levels in a panel of 22 glioblastomas. These data 
      demonstrate that the phosphorylation status of hnRNP A1 serine 199 regulates the 
      AKT-dependent sensitivity of cells to rapamycin and functionally links 
      IRES-transacting factor annealing activity to cellular responses to mTOR complex 
      1 inhibition.
FAU - Martin, Jheralyn
AU  - Martin J
AD  - Department of Research & Development, Greater Los Angeles Veterans Affairs 
      Healthcare System, Los Angeles, California 91343, USA.
FAU - Masri, Janine
AU  - Masri J
FAU - Cloninger, Cheri
AU  - Cloninger C
FAU - Holmes, Brent
AU  - Holmes B
FAU - Artinian, Nicholas
AU  - Artinian N
FAU - Funk, Alexander
AU  - Funk A
FAU - Ruegg, Teresa
AU  - Ruegg T
FAU - Anderson, Lauren
AU  - Anderson L
FAU - Bashir, Tariq
AU  - Bashir T
FAU - Bernath, Andrew
AU  - Bernath A
FAU - Lichtenstein, Alan
AU  - Lichtenstein A
FAU - Gera, Joseph
AU  - Gera J
LA  - eng
GR  - R01CA111448/CA/NCI NIH HHS/United States
GR  - R01 CA109312/CA/NCI NIH HHS/United States
GR  - R01CA109312/CA/NCI NIH HHS/United States
GR  - R01 CA111448/CA/NCI NIH HHS/United States
GR  - R01 CA132778/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 - 20110316
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Heterogeneous Nuclear Ribonucleoprotein A1)
RN  - 0 (Heterogeneous-Nuclear Ribonucleoprotein Group A-B)
RN  - 0 (Hnrnpa1 protein, mouse)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (hnRNPA1 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - *Amino Acid Substitution
MH  - Animals
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/*drug effects/genetics
MH  - Glioblastoma/genetics/*metabolism
MH  - Heterogeneous Nuclear Ribonucleoprotein A1
MH  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/*metabolism
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes
MH  - Mutation, Missense
MH  - Phosphorylation/drug effects/genetics
MH  - Protein Biosynthesis/drug effects/genetics
MH  - Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
PMC - PMC3091246
EDAT- 2011/04/02 06:00
MHDA- 2011/07/02 06:00
PMCR- 2012/05/06
CRDT- 2011/04/02 06:00
PHST- 2011/04/02 06:00 [entrez]
PHST- 2011/04/02 06:00 [pubmed]
PHST- 2011/07/02 06:00 [medline]
PHST- 2012/05/06 00:00 [pmc-release]
AID - S0021-9258(20)51456-7 [pii]
AID - M110.205096 [pii]
AID - 10.1074/jbc.M110.205096 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 May 6;286(18):16402-13. doi: 10.1074/jbc.M110.205096. Epub 2011 
      Mar 16.