Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-06, Vol.66 (11), p.5707-5715
• Main Authors: SCHNEPP, Robert W, CHEN, Ya-Xiong, HAOREN WANG, CASH, Tim, SILVA, Albert, DIEHL, J. Alan, BROWN, Eric, XIANXIN HUA
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Growth Processes - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cyclin-Dependent Kinase Inhibitor p18 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Embryo, Mammalian; Fibroblasts - cytology; Fibroblasts - metabolism; Fibroblasts - physiology; Genes, Tumor Suppressor; Humans; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Medical sciences; Mice; Pharmacology. Drug treatments; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; S Phase - genetics; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-4518

Multiple endocrine neoplasia type 1 (MEN1), an inherited tumor syndrome affecting endocrine organs including pancreatic islets, results from mutation of the tumor suppressor gene Men1 that encodes protein menin. Although menin is known to be involved in regulating cell proliferation in vitro, it is not clear how menin regulates cell cycle and whether mutation of Men1 acutely promotes pancreatic islet cell proliferation in vivo. Here we show that excision of the floxed Men1 in mouse embryonic fibroblasts (MEF) accelerates G(0)/G(1) to S phase entry. This accelerated S-phase entry is accompanied by increased cyclin-dependent kinase 2 (CDK2) activity as well as decreased expression of CDK inhibitors p18(Ink4c) and p27(Kip1). Moreover, Men1 excision results in decreased expression of p18(Ink4c) and p27(Kip1) in the pancreas. Furthermore, complementation of menin-null cells with wild-type menin represses S-phase entry. To extend the role of menin in repressing cell cycle in cultured cells to in vivo pancreatic islets, we generated a system in which floxed Men1 alleles can be excised in a temporally controllable manner. As early as 7 days following Men1 excision, pancreatic islet cells display increased proliferation, leading to detectable enlargement of pancreatic islets 14 days after Men1 excision. These observations are consistent with the notion that an acute effect of Men1 mutation is accelerated S-phase entry and enhanced cell proliferation in pancreatic islets. Together, these results suggest a molecular mechanism whereby menin suppresses MEN1 tumorigenesis at least partly through repression of G(0)/G(1) to S transition.