PMID- 26709830 OWN - NLM STAT- MEDLINE DCOM- 20160706 LR - 20200902 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 12 DP - 2015 TI - 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. PG - e0145792 LID - 10.1371/journal.pone.0145792 [doi] LID - e0145792 AB - 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. FAU - McKimpson, Wendy M AU - McKimpson WM AD - Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. FAU - Yuan, Ziqiang AU - Yuan Z AD - Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. FAU - Zheng, Min AU - Zheng M AD - Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. FAU - Crabtree, Judy S AU - Crabtree JS AD - Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States of America. FAU - Libutti, Steven K AU - Libutti SK AD - Department of Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. FAU - Kitsis, Richard N AU - Kitsis RN AD - Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. AD - Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States of America. LA - eng GR - P30CA013330/CA/NCI NIH HHS/United States GR - R01HL060665/HL/NHLBI NIH HHS/United States GR - P30 DK041296/DK/NIDDK NIH HHS/United States GR - R01 HL060665/HL/NHLBI NIH HHS/United States GR - R01CA170911/CA/NCI NIH HHS/United States GR - T32GM007491/GM/NIGMS NIH HHS/United States GR - T32 GM007491/GM/NIGMS NIH HHS/United States GR - R01 CA170911/CA/NCI NIH HHS/United States GR - P30 CA013330/CA/NCI NIH HHS/United States GR - P30DK020541/DK/NIDDK NIH HHS/United States GR - P50 CA174521/CA/NCI NIH HHS/United States GR - UL1 TR001073/TR/NCATS NIH HHS/United States GR - P30 DK020541/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151228 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Men1 protein, mouse) RN - 0 (Muscle Proteins) RN - 0 (Nol3 protein, mouse) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Messenger) RN - 0 (RNA, Neoplasm) SB - IM MH - Animals MH - Apoptosis Regulatory Proteins/*biosynthesis/deficiency/genetics MH - Female MH - Gene Deletion MH - Genes, Tumor Suppressor MH - Insulinoma/genetics/metabolism/pathology MH - Male MH - Mice MH - Mice, 129 Strain MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Multiple Endocrine Neoplasia Type 1/genetics/metabolism/pathology MH - Muscle Proteins/*biosynthesis/deficiency/genetics MH - Pancreas/metabolism/pathology MH - Pancreatic Neoplasms/genetics/metabolism/pathology MH - Proto-Oncogene Proteins/*deficiency/*genetics MH - RNA, Messenger/genetics/metabolism MH - RNA, Neoplasm/genetics/metabolism MH - Tissue Distribution PMC - PMC4692498 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/12/29 06:00 MHDA- 2016/07/07 06:00 PMCR- 2015/12/28 CRDT- 2015/12/29 06:00 PHST- 2015/09/16 00:00 [received] PHST- 2015/12/08 00:00 [accepted] PHST- 2015/12/29 06:00 [entrez] PHST- 2015/12/29 06:00 [pubmed] PHST- 2016/07/07 06:00 [medline] PHST- 2015/12/28 00:00 [pmc-release] AID - PONE-D-15-40995 [pii] AID - 10.1371/journal.pone.0145792 [doi] PST - epublish SO - PLoS One. 2015 Dec 28;10(12):e0145792. doi: 10.1371/journal.pone.0145792. eCollection 2015.