Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in multiple solid tumor types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Integrative analysis of the region identifies 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 TOR signaling. Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. Thus, reinforcing genomic and genetic, biological, functional and biochemical data in yeast and humans establish GOLPH3 as a novel oncogene that is commonly targeted for amplification in human cancer and capable of modulating the response to rapamycin, a cancer drug in clinical use.

Glioblastoma multiforme (GBM) is the most common and lethal primary brain cancer that is driven by aberrant signaling of growth factor receptors, particularly the epidermal growth factor receptor (EGFR). EGFR signaling is tightly regulated by receptor endocytosis and lysosome-mediated degradation, although the molecular mechanisms governing such regulation, particularly in the context of cancer, remain poorly delineated. Here, high-resolution genomic profiles of GBM identified a highly recurrent focal 1p36 deletion encompassing the putative tumor suppressor gene, Mig-6. We show that Mig-6 quells the malignant potential of GBM cells and dampens EGFR signaling by driving EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation. Mechanistically, this effect is mediated by the binding of Mig-6 to a SNARE protein STX8, a protein known to be required for late endosome trafficking. Thus, Mig-6 functions to ensure recruitment of internalized receptor to late endosomes and subsequently the lysosomal degradation compartment through its ability to specifically link EGFR and STX8 during ligand-stimulated EGFR trafficking. In GBM, the highly frequent loss of Mig-6 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Together, these data uncover a unique tumor suppression mechanism involving the regulation of receptor trafficking.

Abstract-The widespread deployment of wireless networks presents an opportunity for localization and mapping using only signal-strength measurements. The current state of the art is to use Gaussian process latent variable models (GP-LVM). This method works well, but relies on a signature uniqueness assumption which limits its applicability to only signal-rich environments. Moreover, it does not scale computationally to large sets of data, requiring O N 3 operations per iteration. We present a GraphSLAM-like algorithm for signal strength SLAM. Our algorithm shares many of the benefits of Gaussian processes, yet is viable for a broader range of environments since it makes no signature uniqueness assumptions. It is also more tractable to larger map sizes, requiring O N 2 operations per iteration. We compare our algorithm to a laser-SLAM ground truth, showing it produces excellent results in practice.

Controversy exists regarding the expression of specific steroid receptor proteins and mRNA in human microvascular endometrial endothelial cells (HEECs). Thus, we studied steroid receptor expression in early passaged HEEC cultures and freshly isolated HEECs. Analysis of estrogen receptor (ER) and progesterone receptor (PR) mRNA levels was carried out with real-time quantitative RT-PCR, and the repertoire of genes activated by their respective steroid ligands was assessed by mRNA microarray analyses of 18,400 genes and expressed sequence tags. We observed that cultured and freshly isolated HEECs each express ER-beta mRNA but not ER-alpha. In addition, PR mRNA was also detectable in both HEEC sources. Microarray analysis demonstrated that treatment of HEEC cultures with either estradiol or medroxyprogesterone acetate produced differential effects on a wide variety of genes, and cluster analysis demonstrated that many of the genes are involved in intracellular signaling and enzymatic pathways. Thus, quantitative RT-PCR and microarray analyses demonstrate that HEECs express ER-beta and PR mRNA and that gene expression by HEECs is differentially regulated by treatment with estrogen or progestin.

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