PMID- 23322780
OWN - NLM
STAT- MEDLINE
DCOM- 20130509
LR  - 20211203
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 9
DP  - 2013 Mar 1
TI  - Mutations in critical domains confer the human mTOR gene strong tumorigenicity.
PG  - 6511-21
LID - 10.1074/jbc.M112.399485 [doi]
AB  - Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that 
      regulates cell growth, proliferation, and survival. mTOR is frequently activated 
      in human cancers and is a commonly sought anticancer therapeutic target. However, 
      whether the human mTOR gene itself is a proto-oncogene possessing tumorigenicity 
      has not been firmly established. To answer this question, we mutated 
      evolutionarily conserved amino acids, generated eight mutants in the HEAT repeats 
      (M938T) and the FAT (W1456R and G1479N) and kinase (P2273S, V2284M, V2291I, 
      T2294I, and E2288K) domains of mTOR, and studied their oncogenicity. On transient 
      expression in HEK293T cells, these mTOR mutants displayed elevated protein kinase 
      activities accompanied by activated mTOR/p70S6K signaling at varying levels, 
      demonstrating the gain of function of the mTOR gene with these mutations. We 
      selected P2273S and E2288K, the two most catalytically active mutants, to further 
      examine their oncogenicity and tumorigenicity. Stable expression of the two mTOR 
      mutants in NIH3T3 cells strongly activated mTOR/p70S6K signaling, induced cell 
      transformation and invasion, and remarkably, caused rapid tumor formation and 
      growth in athymic nude mice after subcutaneous inoculation of the transfected 
      cells. This study confirms the oncogenic potential of mTOR suggested previously 
      and demonstrates for the first time its tumorigenicity. Thus, beyond the pivotal 
      position of mTOR to relay the oncogenic signals from the upstream 
      phosphatidylinositol 3-kinase/Akt pathway in human cancer, mTOR is capable 
      potentially of playing a direct role in human tumorigenesis if mutated. These 
      results also further support the conclusion that mTOR is a major therapeutic 
      target in human cancers.
FAU - Murugan, Avaniyapuram Kannan
AU  - Murugan AK
AD  - Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology 
      and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 
      21287, USA.
FAU - Alzahrani, Ali
AU  - Alzahrani A
FAU - Xing, Mingzhao
AU  - Xing M
LA  - eng
GR  - R01 CA134225/CA/NCI NIH HHS/United States
GR  - R01CA134225/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130115
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Cell Line
MH  - Cell Transformation, Neoplastic/genetics/*metabolism/pathology
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - *Mutation, Missense
MH  - Neoplasm Invasiveness
MH  - Neoplasm Transplantation
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Mas
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Transplantation, Heterologous
PMC - PMC3585084
EDAT- 2013/01/17 06:00
MHDA- 2013/05/10 06:00
PMCR- 2014/03/01
CRDT- 2013/01/17 06:00
PHST- 2013/01/17 06:00 [entrez]
PHST- 2013/01/17 06:00 [pubmed]
PHST- 2013/05/10 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - S0021-9258(20)43541-0 [pii]
AID - M112.399485 [pii]
AID - 10.1074/jbc.M112.399485 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Mar 1;288(9):6511-21. doi: 10.1074/jbc.M112.399485. Epub 2013 
      Jan 15.