PMID- 16195383
OWN - NLM
STAT- MEDLINE
DCOM- 20060420
LR  - 20181201
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 102
IP  - 41
DP  - 2005 Oct 11
TI  - Menin regulates pancreatic islet growth by promoting histone methylation and 
      expression of genes encoding p27Kip1 and p18INK4c.
PG  - 14659-64
AB  - Menin, the product of the Men1 gene mutated in familial multiple endocrine 
      neoplasia type 1 (MEN1), regulates transcription in differentiated cells. Menin 
      associates with and modulates the histone methyltransferase activity of a nuclear 
      protein complex to activate gene expression. However, menin-dependent histone 
      methyltransferase activity in endocrine cells has not been demonstrated, and the 
      mechanism of endocrine tumor suppression by menin remains unclear. Here, we show 
      that menin-dependent histone methylation maintains the in vivo expression of 
      cyclin-dependent kinase (CDK) inhibitors to prevent pancreatic islet tumors. In 
      vivo expression of CDK inhibitors, including p27 and p18, and other cell cycle 
      regulators is disrupted in mouse islet tumors lacking menin. Chromatin 
      immunoprecipitation studies reveal that menin directly associates with regions of 
      the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in 
      histone H3 associated with these promoters. Moreover, H3 Lys-4 methylation 
      associated with p27 and p18 is reduced in islet tumors from Men1 mutant mice. 
      Thus, H3 Lys-4 methylation is a crucial function of menin in islet tumor 
      suppression. These studies suggest an epigenetic mechanism of tumor suppression: 
      by promoting histone modifications, menin maintains transcription at multiple 
      loci encoding cell cycle regulators essential for endocrine growth control.
FAU - Karnik, Satyajit K
AU  - Karnik SK
AD  - Departments of Developmental Biology and Medicine (Oncology Division), Stanford 
      University School of Medicine, Stanford, CA 94305-5329.
FAU - Hughes, Christina M
AU  - Hughes CM
FAU - Gu, Xueying
AU  - Gu X
FAU - Rozenblatt-Rosen, Orit
AU  - Rozenblatt-Rosen O
FAU - McLean, Graeme W
AU  - McLean GW
FAU - Xiong, Yue
AU  - Xiong Y
FAU - Meyerson, Matthew
AU  - Meyerson M
FAU - Kim, Seung K
AU  - Kim SK
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20050929
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p18)
RN  - 0 (Histones)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.1.1.- (Histone Methyltransferases)
RN  - EC 2.1.1.- (Protein Methyltransferases)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Chromatin Immunoprecipitation
MH  - Cyclin-Dependent Kinase Inhibitor p18/*biosynthesis
MH  - Cyclin-Dependent Kinase Inhibitor p27/*biosynthesis
MH  - *Gene Expression Regulation
MH  - Genes, Tumor Suppressor/*physiology
MH  - Histone Methyltransferases
MH  - Histone-Lysine N-Methyltransferase/*metabolism
MH  - Histones/metabolism
MH  - Islets of Langerhans/*growth & development/metabolism
MH  - Luciferases
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiple Endocrine Neoplasia Type 1/metabolism
MH  - Protein Methyltransferases
MH  - Proto-Oncogene Proteins/*physiology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Cells, Cultured
PMC - PMC1253549
EDAT- 2005/10/01 09:00
MHDA- 2006/04/21 09:00
PMCR- 2006/04/11
CRDT- 2005/10/01 09:00
PHST- 2005/10/01 09:00 [pubmed]
PHST- 2006/04/21 09:00 [medline]
PHST- 2005/10/01 09:00 [entrez]
PHST- 2006/04/11 00:00 [pmc-release]
AID - 0503484102 [pii]
AID - 010214659 [pii]
AID - 10.1073/pnas.0503484102 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14659-64. doi: 
      10.1073/pnas.0503484102. Epub 2005 Sep 29.