Large scale genetic screen identifies MAP17 as protein bypassing TNF-induced growth arrest.
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.
Guijarro
M V
MV
Experimental Therapeutics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Castro
M E
ME
Romero
L
L
Moneo
V
V
Carnero
A
A
D018270:Carcinoma, Ductal, Breast / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002472:Cell Transformation, Viral; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression; D005820:Genetic Testing; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D008565:Membrane Proteins; C509768:PDZK1IP1 protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha