TY - JOUR
T1 - G0LPH3 modulates mTOR signalling and rapamydn sensitivity in cancer
AU - Scott, Kenneth L.
AU - Kabbarah, Omar
AU - Liang, Mei Chih
AU - Ivanova, Elena
AU - Anagnostou, Valsamo
AU - Wu, Joyce
AU - Dhakal, Sabin
AU - Wu, Min
AU - Chen, Shujuan
AU - Feinberg, Tamar
AU - Huang, Joseph
AU - Saci, Abdel
AU - Widlund, Hans R.
AU - Fisher, David E.
AU - Xiao, Yonghong
AU - Rimm, David L.
AU - Protopopov, Alexei
AU - Wong, Kwok Kin
AU - Chin, Lynda
PY - 2009/6/25
Y1 - 2009/6/25
N2 - Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the rrans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAPI) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.
AB - Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the rrans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAPI) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.
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U2 - 10.1038/nature08109
DO - 10.1038/nature08109
M3 - Article
C2 - 19553991
AN - SCOPUS:67649500009
SN - 0028-0836
VL - 459
SP - 1085
EP - 1090
JO - Nature
JF - Nature
IS - 7250
ER -