PMID- 21326806
OWN - NLM
STAT- MEDLINE
DCOM- 20110614
LR  - 20211203
IS  - 1936-2625 (Electronic)
IS  - 1936-2625 (Linking)
VI  - 4
IP  - 2
DP  - 2010 Jan 28
TI  - Constitutive activation with overexpression of the mTORC2-phospholipase D1 
      pathway in uterine leiomyosarcoma and STUMP: morphoproteomic analysis with 
      therapeutic implications.
PG  - 134-46
AB  - The mammalian target of rapamycin (mTOR) is centrally involved in growth, 
      survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a 
      clinically validated target for therapy and drug development. Biologically, mTOR 
      acts as the catalytic subunit of two functionally distinct complexes, called mTOR 
      complex 1 (mTORC1) which is predominantly cytoplasmic in subcellular localization 
      and mTOR complex 2 (mTORC2) which is both cytoplasmic and nuclear. mTORC1 is 
      sensitive to the selective inhibitor rapamycin. By contrast, mTORC2 is relatively 
      resistant to rapamycin. Moreover, its putative downstream effector, Akt 
      phosphorylated on serine 473 represents a signal transduction pathway for tumor 
      survival. Phospholipase D (PLD) and its product, phosphatidic acid (PA) have been 
      implicated as an activator of mTOR signaling, including the direct 
      phosphorylative activation of p70S6K atthreonine 389. The latter promotes cell 
      cycle progression. In this study, we investigated the activation status and 
      subcellular localization of mTOR and the relative expression of PLD1, as well as 
      their downstream effectors in a spectrum of uterine smooth muscle tumors using 
      normal myometria as controls. The results show significant activation with 
      overexpression of phosphorylated mTORC2 complex in uterine leiomyosarcoma (ULMS) 
      and smooth muscle tumors of uncertain malignant potential (STUMP) as evidenced by 
      nuclear localization of p-mTOR (Ser 2448) in ULMS>STUMP>uterine leiomyoma and 
      normal myometria (p<0.05) and with overexpression of PLD1(p<0.05). 
      Cor-relatively, there are overexpressions of nuclear p-Akt (Ser 473) and nuclear 
      p-p70S6K (Thr 389) in ULMS and STUMP (p<0.05). The activation with overexpression 
      of components of the mTORC2-PLD1 pathway in ULMS and to a lesser degree in STUMP 
      provides insight into their tumorigenic mechanisms. Thus the development of 
      therapies designed to target mTORC2 and PLD1 activity may be beneficial in 
      treating ULMS.
FAU - Dhingra, Sadhna
AU  - Dhingra S
AD  - Department of Pathology and Laboratory Medicine, UT Health- Medical School at 
      Houston, 6431 Fannin St, Houston, TX 77030, USA.
FAU - Rodriguez, Michelle E
AU  - Rodriguez ME
FAU - Shen, Qi
AU  - Shen Q
FAU - Duan, Xuizhen
AU  - Duan X
FAU - Stanton, Melissa L
AU  - Stanton ML
FAU - Chen, Lei
AU  - Chen L
FAU - Zhang, Rongzhen
AU  - Zhang R
FAU - Brown, Robert E
AU  - Brown RE
LA  - eng
PT  - Journal Article
DEP - 20100128
PL  - United States
TA  - Int J Clin Exp Pathol
JT  - International journal of clinical and experimental pathology
JID - 101480565
RN  - 0 (Biomarkers, Tumor)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.4.4 (Phospholipase D)
RN  - EC 3.1.4.4 (phospholipase D1)
SB  - IM
MH  - Biomarkers, Tumor/metabolism
MH  - Cell Nucleus/metabolism/pathology
MH  - Disease Progression
MH  - Female
MH  - Fluorescent Antibody Technique, Indirect
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Leiomyosarcoma/*metabolism/pathology
MH  - Myometrium/metabolism
MH  - Phospholipase D/*metabolism
MH  - Phosphorylation
MH  - Prognosis
MH  - Proteomics
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tissue Array Analysis
MH  - Uterine Neoplasms/*metabolism/pathology
PMC - PMC3037199
OTO - NOTNLM
OT  - Morphoproteomics
OT  - STUMP
OT  - mTORC2
OT  - phospholipase D1
OT  - uterine leiomyosarcoma
EDAT- 2011/02/18 06:00
MHDA- 2011/06/15 06:00
PMCR- 2010/01/28
CRDT- 2011/02/18 06:00
PHST- 2011/01/24 00:00 [received]
PHST- 2010/01/26 00:00 [accepted]
PHST- 2011/02/18 06:00 [entrez]
PHST- 2011/02/18 06:00 [pubmed]
PHST- 2011/06/15 06:00 [medline]
PHST- 2010/01/28 00:00 [pmc-release]
PST - epublish
SO  - Int J Clin Exp Pathol. 2010 Jan 28;4(2):134-46.