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Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chen, Ya-Xiong Wang, Haoren Cash, Tim Silva, Albert Mello E. Diehl, J. Alan Brown, Eric Hua, Xianxin |
| Copyright Year | 2006 |
| Abstract | 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/66/11/5707.full.pdf |
| PubMed reference number | 16740708v1 |
| Volume Number | 66 |
| Issue Number | 11 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Carcinogenesis Cell Cycle Cell Proliferation Cyclins Endocrine Gland Neoplasms Excision Genes, Suppressor Hypertrophy Islets of Langerhans MEN1 gene Multiple Endocrine Neoplasia Type 1 Mutation Neoplastic disease Null Value Null cell Organ Repression, Psychology Tumor Suppressor Genes |
| Content Type | Text |
| Resource Type | Article |
