title: The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth.
abstract: Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder characterized by tissue-specific tumors in the endocrine pancreas, parathyroid, and pituitary glands. Although tumor development in these tissues is dependent upon genetic inactivation of the tumor suppressor Men1, loss of both alleles of this gene is not sufficient to induce these cancers. Men1 encodes menin, a nuclear protein that influences transcription. A previous ChIP on chip analysis suggested that menin binds promoter sequences of nol3, encoding ARC, which is a cell death inhibitor that has been implicated in cancer pathogenesis. We hypothesized that ARC functions as a co-factor with Men1 loss to induce the tissue-restricted distribution of tumors seen in MEN1. Using mouse models that recapitulate this syndrome, we found that biallelic deletion of Men1 results in selective induction of ARC expression in tissues that develop tumors. Specifically, loss of Men1 in all cells of the pancreas resulted in marked increases in ARC mRNA and protein in the endocrine, but not exocrine, pancreas. Similarly, ARC expression increased in the parathyroid with inactivation of Men1 in that tissue. To test if ARC contributes to MEN1 tumor development in the endocrine pancreas, we generated mice that lacked none, one, or both copies of ARC in the context of Men1 deletion. Studies in a cohort of 126 mice demonstrated that, although mice lacking Men1 developed insulinomas as expected, elimination of ARC in this context did not significantly alter tumor load. Cellular rates of proliferation and death in these tumors were also not perturbed in the absence of ARC. These results indicate that ARC is upregulated by loss Men1 in the tissue-restricted distribution of MEN1 tumors, but that ARC is not required for tumor development in this syndrome.
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: McKimpson
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States of America.
authors.forename: Judy S
authors.initials: JS
authors.lastname: Crabtree
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.|Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D051017:Apoptosis Regulatory Proteins; C484898:Men1 protein, mouse; D009124:Muscle Proteins; C491787:Nol3 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm