Large scale genetic screen identifies MAP17 as protein bypassing TNF‐induced growth arrest

Abstract

Although activated macrophages destroy cancer cells more effectively than normal cells, the ability to escape activated macrophages is a characteristic of tumor cells. One of the mechanisms responsible for the specific killing of tumor cells by macrophages is the production of the cytokine tumor necrosis factor (TNF) alpha. Therefore, resistance to TNF may provide such cancer cells a selective advantage against host elimination. With the aim of identifying genes with these properties we undertook a large scale genetic screen to identify genes able to bypass TNF-induced G1 arrest. We identified MAP17, a small 17 kDa nonglycosylated membrane protein that localizes to the plasma membrane and the Golgi apparatus. Ectopic expression of MAP17 in tumor cells prevents TNF-induced G1 arrest by impairing p21waf1 induction. However, expression of MAP17 does not inhibit TNF-induced apoptosis in Me180-sensitive tumor cells. The inhibition of TNF is specific since MAP17 does not alter the response to other cytokines such as IFNgamma. As described in the Xenopus oocyte system, MAP17 increases the uptake of mannose in some cells, but this effect is not responsible for TNF bypass. We have also analyzed the expression of MAP17 mRNA in a panel of cell lines. MAP17 is expressed in 30% of cell lines of different origin. However, MAP17 mRNA expression did not correlate with TNF resistance. Our data indicates that although MAP17 expression might bypass TNF-induced growth arrest, it is not the only determinant of this response.

The Lysosomal Transmembrane Protein 9B Regulates the Activity of Inflammatory Signaling Pathways

“…We sought therefore to determine whether TMEM9B regulated TNF-induced apoptosis. The ME180 cell line is sensitive to TNF-induced apoptosis (13), and treatment with TNF resulted in about 20 and 30% dead cells (after 10 and 100 ng/ml TNF, respectively; Fig. 5A).…”

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

“…Our serous LMP dataset was approximately equally split into high-grade (n = 13) and lowgrade (n = 12) samples. Eight genes that were overexpressed in high-grade serous LMP tumors were identified (Supplementary Table S4C), including LST1, which is involved in the enhancement of MEK and ERK1/2 signaling through targeting of ERK-MAPK pathway components to the actin cytoskeleton (26); PDZK1IP1 (MAP17), which may act to bypass tumor necrosis factor (TNF) -induced G 1 arrest (27); and GPNMB (Osteoactivin). Osteoactivin is expressed in advanced malignancies of varying origins (28) and enhances metastatic behavior in human glioma cell line models (29).…”

MAP17 and the double-edged sword of ROS

“…A genome-wide retroviral cDNA screen to search for genes that confer a selective advantage to cancer cells during tumorigenesis allowed us to identify MAP17 [47]. MAP17 is a small, non-glycosylated, membrane-associated 17-kDa protein that localizes to the plasma membrane and the Golgi apparatus [48].…”