PMID- 16740708
OWN - NLM
STAT- MEDLINE
DCOM- 20060727
LR  - 20181113
IS  - 0008-5472 (Print)
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 11
DP  - 2006 Jun 1
TI  - Mutation of tumor suppressor gene Men1 acutely enhances proliferation of 
      pancreatic islet cells.
PG  - 5707-15
AB  - 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.
FAU - Schnepp, Robert W
AU  - Schnepp RW
AD  - Abramson Family Cancer Research Institute, Department of Cancer Biology, 
      University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
FAU - Chen, Ya-Xiong
AU  - Chen YX
FAU - Wang, Haoren
AU  - Wang H
FAU - Cash, Tim
AU  - Cash T
FAU - Silva, Albert
AU  - Silva A
FAU - Diehl, J Alan
AU  - Diehl JA
FAU - Brown, Eric
AU  - Brown E
FAU - Hua, Xianxin
AU  - Hua X
LA  - eng
GR  - R01 CA113962/CA/NCI NIH HHS/United States
GR  - R01 CA100912-04/CA/NCI NIH HHS/United States
GR  - R01 CA100912/CA/NCI NIH HHS/United States
GR  - R01 CA113962-02/CA/NCI NIH HHS/United States
GR  - CA100912/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Cdkn1b protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p18)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
SB  - IM
MH  - Animals
MH  - Cell Growth Processes/genetics
MH  - Cyclin-Dependent Kinase 2/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p18/genetics/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism
MH  - Embryo, Mammalian
MH  - Fibroblasts/cytology/metabolism/physiology
MH  - *Genes, Tumor Suppressor
MH  - Humans
MH  - Islets of Langerhans/*cytology/metabolism/physiology
MH  - Mice
MH  - Proto-Oncogene Proteins/deficiency/*genetics
MH  - S Phase/genetics
PMC - PMC2839933
MID - NIHMS183850
EDAT- 2006/06/03 09:00
MHDA- 2006/07/28 09:00
PMCR- 2010/03/16
CRDT- 2006/06/03 09:00
PHST- 2006/06/03 09:00 [pubmed]
PHST- 2006/07/28 09:00 [medline]
PHST- 2006/06/03 09:00 [entrez]
PHST- 2010/03/16 00:00 [pmc-release]
AID - 66/11/5707 [pii]
AID - 10.1158/0008-5472.CAN-05-4518 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Jun 1;66(11):5707-15. doi: 10.1158/0008-5472.CAN-05-4518.