PMID- 17914450
OWN - NLM
STAT- MEDLINE
DCOM- 20080402
LR  - 20211203
IS  - 1523-1747 (Electronic)
IS  - 0022-202X (Linking)
VI  - 128
IP  - 4
DP  - 2008 Apr
TI  - mTOR is activated in the majority of malignant melanomas.
PG  - 980-7
AB  - The objective of this study was to determine whether activation of the kinase 
      mammalian target of rapamycin (mTOR) is associated with human melanoma. We found 
      moderate or strong hyperphosphorylation of ribosomal protein S6 in 78/107 
      melanomas (73%). In contrast, only 3/67 benign nevi (4%) were moderately 
      positive, and none were strongly positive. These data indicate that mTOR 
      activation is very strongly associated with malignant, compared to benign, 
      melanocytic lesions. Next, we tested six melanoma-derived cell lines for evidence 
      of mTOR dysregulation. Five of the six lines showed persistent phosphorylation of 
      S6 after 18 hours of serum deprivation, and four had S6 phosphorylation after 30 
      minutes of amino-acid withdrawal, indicating inappropriate mTOR activation. The 
      proliferation of three melanoma-derived lines was blocked by the mTOR inhibitor 
      rapamycin, indicating that mTOR activation is a growth-promoting factor in 
      melanoma-derived cells. mTOR is directly activated by the small guanosine 
      triphosphatase Ras homolog enriched in brain (Rheb), in a farnesylation-dependent 
      manner. Therefore, to investigate the mechanism of mTOR activation, we used the 
      farnesyl transferase inhibitor FTI-277, which partially blocked the growth of 
      three of the six melanoma cell lines. Together, these data implicate activation 
      of mTOR in the pathogenesis of melanoma, and suggest that Rheb and mTOR may be 
      targets for melanoma therapy.
FAU - Karbowniczek, Magdalena
AU  - Karbowniczek M
AD  - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, 
      Pennsylvania 19111, USA.
FAU - Spittle, Cynthia S
AU  - Spittle CS
FAU - Morrison, Tasha
AU  - Morrison T
FAU - Wu, Hong
AU  - Wu H
FAU - Henske, Elizabeth P
AU  - Henske EP
LA  - eng
GR  - DK 51052/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071004
PL  - United States
TA  - J Invest Dermatol
JT  - The Journal of investigative dermatology
JID - 0426720
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Ribosomal Protein S6)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - DNA Mutational Analysis
MH  - Humans
MH  - Melanoma/*enzymology/genetics/*pathology
MH  - Nevus/enzymology/pathology
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Kinases/drug effects/*metabolism
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Proto-Oncogene Proteins p21(ras)/genetics
MH  - Ribosomal Protein S6/metabolism
MH  - Sirolimus/pharmacology
MH  - Skin Neoplasms/*enzymology/genetics/*pathology
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/10/05 09:00
MHDA- 2008/04/03 09:00
CRDT- 2007/10/05 09:00
PHST- 2007/10/05 09:00 [pubmed]
PHST- 2008/04/03 09:00 [medline]
PHST- 2007/10/05 09:00 [entrez]
AID - S0022-202X(15)33802-1 [pii]
AID - 10.1038/sj.jid.5701074 [doi]
PST - ppublish
SO  - J Invest Dermatol. 2008 Apr;128(4):980-7. doi: 10.1038/sj.jid.5701074. Epub 2007 
      Oct 4.