PMID- 15150273
OWN - NLM
STAT- MEDLINE
DCOM- 20041026
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 39
DP  - 2004 Sep 24
TI  - Menin is required for bone morphogenetic protein 2- and transforming growth 
      factor beta-regulated osteoblastic differentiation through interaction with Smads 
      and Runx2.
PG  - 40267-75
AB  - Menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, is 
      required for commitment of multipotential mesenchymal stem cells to the 
      osteoblast lineage, however, it inhibits their later differentiation (Sowa, H., 
      Kaji, H., Canaff, L., Hendy, G.N., Tsukamoto, T., Yamaguchi, T., Miyazono, K., 
      Sugimoto, T., and Chihara, K. (2003) J. Biol. Chem. 278, 21058-21069). Here, we 
      have examined the mechanism of action of menin in regulating osteoblast 
      differentiation using the mouse bone marrow stromal ST2 and osteoblast MC3T3-E1 
      cell lines. In ST2 cells, reduced menin expression achieved by transfection of 
      menin antisense DNA (AS) antagonized bone morphogenetic protein (BMP)-2-induced 
      alkaline phosphatase activity and osteocalcin and Runx2 mRNA expression. Menin 
      was co-immunoprecipitated with Smad1/5 in ST2 and MC3T3-E1 cells, and 
      inactivation of menin antagonized BMP-2-induced transcriptional activity of 
      Smad1/5 in ST2 cells, but not MC3T3-E1 cells. Menin was co-immunoprecipitated 
      with the key osteoblast regulator, Runx2, and AS antagonized Runx2 
      transcriptional activity and the ability of Runx2 to stimulate alkaline 
      phosphatase activity only in ST2 cells but not in MC3T3-E1 cells. In the 
      osteoblast MC3T3-E1 cells, transforming growth factor-beta and its signaling 
      molecule, Smad3, negatively regulated Runx2 transcriptional activity. Menin and 
      Smad3 were co-immunoprecipitated, and combined menin and Smad3 overexpression 
      antagonized, whereas menin and the dominant-negative Smad3DeltaC together 
      enhanced BMP-2-induced transcriptional activity of Smad1/5 and Runx2. Smad3 alone 
      had no effect. Therefore, menin interacts physically and functionally with Runx2 
      in uncommitted mesenchymal stem cells, but not in well differentiated 
      osteoblasts. In osteoblasts the interaction of menin and the transforming growth 
      factor-beta/Smad3 pathway negatively regulates the BMP-2/Smad1/5- and 
      Runx2-induced transcriptional activities leading to inhibition of late-stage 
      differentiation.
CI  - Copyright 2004 American Society for Biochemistry and Molecular Biology, Inc.
FAU - Sowa, Hideaki
AU  - Sowa H
AD  - Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, 
      Department of Clinical Molecular Medicine, Kobe University Graduate School of 
      Medicine, Kobe 6500017, Japan.
FAU - Kaji, Hiroshi
AU  - Kaji H
FAU - Hendy, Geoffrey N
AU  - Hendy GN
FAU - Canaff, Lucie
AU  - Canaff L
FAU - Komori, Toshihisa
AU  - Komori T
FAU - Sugimoto, Toshitsugu
AU  - Sugimoto T
FAU - Chihara, Kazuo
AU  - Chihara K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040518
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (BMP2 protein, human)
RN  - 0 (Bmp2 protein, mouse)
RN  - 0 (Bone Morphogenetic Protein 2)
RN  - 0 (Bone Morphogenetic Proteins)
RN  - 0 (Core Binding Factor Alpha 1 Subunit)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 0 (SMAD1 protein, human)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (SMAD5 protein, human)
RN  - 0 (Smad Proteins)
RN  - 0 (Smad1 Protein)
RN  - 0 (Smad1 protein, mouse)
RN  - 0 (Smad3 Protein)
RN  - 0 (Smad3 protein, mouse)
RN  - 0 (Smad5 Protein)
RN  - 0 (Smad5 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (recombinant human bone morphogenetic protein-2)
RN  - 63231-63-0 (RNA)
RN  - 9007-49-2 (DNA)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
SB  - IM
MH  - 3T3 Cells
MH  - Alkaline Phosphatase/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Bone Morphogenetic Protein 2
MH  - Bone Morphogenetic Proteins/*metabolism
MH  - Cell Differentiation
MH  - Cell Line
MH  - Core Binding Factor Alpha 1 Subunit
MH  - DNA/chemistry
MH  - DNA-Binding Proteins/metabolism
MH  - Genes, Reporter
MH  - Humans
MH  - Luciferases/metabolism
MH  - Mice
MH  - Models, Biological
MH  - Neoplasm Proteins/*metabolism
MH  - Oligonucleotides, Antisense/chemistry
MH  - Osteoblasts/*cytology/metabolism
MH  - Phosphoproteins/metabolism
MH  - Plasmids/metabolism
MH  - Precipitin Tests
MH  - Proto-Oncogene Proteins/*physiology
MH  - RNA/metabolism
MH  - RNA, Messenger/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Smad Proteins
MH  - Smad1 Protein
MH  - Smad3 Protein
MH  - Smad5 Protein
MH  - Subcellular Fractions
MH  - Time Factors
MH  - Trans-Activators/metabolism
MH  - Transcription Factors/*metabolism
MH  - Transcription, Genetic
MH  - Transfection
MH  - Transforming Growth Factor beta/*metabolism
EDAT- 2004/05/20 05:00
MHDA- 2004/10/27 09:00
CRDT- 2004/05/20 05:00
PHST- 2004/05/20 05:00 [pubmed]
PHST- 2004/10/27 09:00 [medline]
PHST- 2004/05/20 05:00 [entrez]
AID - S0021-9258(20)77106-1 [pii]
AID - 10.1074/jbc.M401312200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Sep 24;279(39):40267-75. doi: 10.1074/jbc.M401312200. Epub 2004 
      May 18.