Identification of a new tumor suppressor gene located at chromosome 8p21.3-22.
Transformation of normal cells into malignant tumor cells, a process termed carcinogenesis, depends on progressive acquisition of genetic alterations. These result in activation of protooncogenes or inactivation of tumor suppressor genes responsible for the loss of proliferative control in tumor cells and the failure to undergo cellular differentiation. The aim of our study was the identification of molecular regulators of carcinogenesis by studying gene expression during induction of cellular differentiation and quiescence in a three-dimensional (3D) cell culture model. Here, we report the discovery of a tumor suppressor gene located at chromosome 8p21.3-22 near marker D8S254. It is ubiquitously expressed in normal tissue and transiently up-regulated during initiation of cellular differentiation and quiescence in 3D cell culture. In contrast, mRNA expression was not detectable in tissue from pancreatic tumor and the pancreatic tumor cell line MIA PaCa-2. Recombinant expression in the tumor cell line MIA PaCa-2 inhibited proliferation, as shown by a 30% reduction of BrdU uptake after recombinant expression. Immunocytochemistry and Western blot analysis of subcellular fractions demonstrated a mitochondrial localization for the mature protein. In conclusion, we identified a tumor suppressor gene at chromosome 8p21.3-22, encoding a mitochondrial protein, controlling cellular proliferation.
Seibold
Stefan
S
Department of Internal Medicine I, Cologne General Hospital, Merheim Medical Center, Medical Faculty University of Cologne, Cologne, Germany. seibold_s@medizin.uni-wuerzburg.de
Rudroff
Claudia
C
Weber
Manfred
M
Galle
Jan
J
Wanner
Christoph
C
Marx
Martin
M
D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002898:Chromosomes, Human, Pair 8; D003001:Cloning, Molecular; D005091:Exons; D016147:Genes, Tumor Suppressor; D006801:Humans; D008928:Mitochondria / Q000737:chemistry; D008954:Models, Biological; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
C474762:MTUS1 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins