PI3K-AKT-mTOR级联是在几乎所有癌症中都活跃的一种重要细胞信号通道，因此也是研究癌症疗法的主要焦点。
现在，在整个基因组范围内进行的一项筛选工作，发现一个以前不知道的致癌基因GOLPH3是被染色体5p13（该染色体与各种不同固体肿瘤相关）上一个放大区域激发的目标。GOLPH3蛋白局限于Golgi网络上，其过度表达刺激S6核糖体激酶-1，后者被mTOR激发，而mTOR则是PI3K-AKT-mTOR级联的一部分，是抗肿瘤药物雷帕霉素的一个作用目标。GOLPH3致癌蛋白在临床前条件下使肌体对雷帕霉素敏感度增加，从而提出一个可能性：它的作用是，充当对雷帕霉素敏感度的一个生物标记。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
