PI3K-AKT-mTOR級(jí)聯(lián)是在幾乎所有癌癥中都活躍的一種重要細(xì)胞信號(hào)通道,，因此也是研究癌癥療法的主要焦點(diǎn)。
現(xiàn)在,，在整個(gè)基因組范圍內(nèi)進(jìn)行的一項(xiàng)篩選工作，發(fā)現(xiàn)一個(gè)以前不知道的致癌基因GOLPH3是被染色體5p13（該染色體與各種不同固體腫瘤相關(guān)）上一個(gè)放大區(qū)域激發(fā)的目標(biāo)。GOLPH3蛋白局限于Golgi網(wǎng)絡(luò)上,，其過度表達(dá)刺激S6核糖體激酶-1,，后者被mTOR激發(fā)，而mTOR則是PI3K-AKT-mTOR級(jí)聯(lián)的一部分,，是抗腫瘤藥物雷帕霉素的一個(gè)作用目標(biāo),。GOLPH3致癌蛋白在臨床前條件下使肌體對(duì)雷帕霉素敏感度增加，從而提出一個(gè)可能性：它的作用是,，充當(dāng)對(duì)雷帕霉素敏感度的一個(gè)生物標(biāo)記,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 459, 1085-1090 (25 June 2009) | doi:10.1038/nature08109
GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer
Kenneth L. Scott1,9, Omar Kabbarah1,9, Mei-Chih Liang1,4, Elena Ivanova2, Valsamo Anagnostou5, Joyce Wu1, Sabin Dhakal1, Min Wu1, Shujuan Chen1, Tamar Feinberg1, Joseph Huang1, Abdel Saci6, Hans R. Widlund3,7, David E. Fisher3,8, Yonghong Xiao2, David L. Rimm5, Alexei Protopopov2, Kwok-Kin Wong1,4 & Lynda Chin1,2,7
1 Department of Medical Oncology,
2 Belfer Institute for Applied Cancer Science,
3 Department of Pediatric Oncology, Dana-Farber Cancer Institute,
4 Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA
5 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
6 Department of Systems Biology, Harvard Medical School,
7 Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
8 Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9 These authors contributed equally to this work.
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 trans-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 FRAP1) 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.
