title: H-REV107-1 stimulates growth in non-small cell lung carcinomas via the activation of mitogenic signaling.
abstract: H-REV107-1, a known member of the class II tumor suppressor gene family, is involved in the regulation of differentiation and survival. We analyzed H-REV107-1 in non-small cell lung carcinomas, in normal lung, and in immortalized and tumor-derived cell lines. Sixty-eight percent of lung tumors revealed positive H-REV107-1-specific staining. Furthermore, survival analysis demonstrated a significant association of cytoplasmic H-REV107-1 with decreased patient survival. This suggested that H-REV107-1, known as a tumor suppressor, plays a different role in non-small cell lung carcinomas. Knock-down of H-REV107-1 expression in lung carcinoma cells inhibited anchorage-dependent and anchorage-independent growth whereas overexpression of H-REV107-1 induced tumor cell proliferation. Consistent with results of the survival analysis, cytoplasmic localization of the protein was essential for this growth-inducing function. Analysis of signaling pathways potentially involved in this process demonstrated that overexpression of H-REV107-1 stimulated RAS-GTPase activity, ERK1,2 phosphorylation, and caveolin-1 expression in the cell lines analyzed. These results indicate that H-REV107-1 is deficient in its function as a tumor suppressor in non-small cell lung carcinomas and is required for proliferation and anchorage-independent growth in cells expressing high levels of the protein, thus contributing to tumor progression in a subset of non-small cell lung carcinomas.
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin Berlin Schumannstr. 20/21, D-10117 Berlin, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Sabine
authors.initials: S
authors.lastname: Fonfara
authors.forename: Raphaela
authors.initials: R
authors.lastname: Guenther
authors.forename: Cornelia
authors.initials: C
authors.lastname: Gieseler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kemmner
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schafer
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D054512:Phospholipases A2, Calcium-Independent; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D048052:Mitogen-Activated Protein Kinase 3; C490065:PLAAT3 protein, human; D054512:Phospholipases A2, Calcium-Independent; D018631:ras Proteins