PMID- 15254225
OWN - NLM
STAT- MEDLINE
DCOM- 20040816
LR  - 20181113
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 24
IP  - 15
DP  - 2004 Aug
TI  - Menin missense mutants associated with multiple endocrine neoplasia type 1 are 
      rapidly degraded via the ubiquitin-proteasome pathway.
PG  - 6569-80
AB  - MEN1 is a tumor suppressor gene that is responsible for multiple endocrine 
      neoplasia type 1 (MEN1) and that encodes a 610-amino-acid protein, called menin. 
      While the majority of germ line mutations identified in MEN1 patients are 
      frameshift and nonsense mutations resulting in truncation of the menin protein, 
      various missense mutations have been identified whose effects on menin activity 
      are unclear. For this study, we analyzed a series of menin proteins with single 
      amino acid alterations and found that all of the MEN1-causing missense mutations 
      tested led to greatly diminished levels of the affected proteins in comparison 
      with wild-type and benign polymorphic menin protein levels. We demonstrate here 
      that the reduced levels of the mutant proteins are due to rapid degradation via 
      the ubiquitin-proteasome pathway. Furthermore, the mutants, but not wild-type 
      menin, interact both with the molecular chaperone Hsp70 and with the 
      Hsp70-associated ubiquitin ligase CHIP, and the overexpression of CHIP promotes 
      the ubiquitination of the menin mutants in vivo. These findings reveal that 
      MEN1-causing missense mutations lead to a loss of function of menin due to 
      enhanced proteolytic degradation, which may be a common mechanism for 
      inactivating tumor suppressor gene products in familial cancer.
FAU - Yaguchi, Hiroko
AU  - Yaguchi H
AD  - Tumor Endocrinology Project, National Cancer Center Research Institute, 5-1-1 
      Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. nohkura@gan2.res.ncc.go.jp
FAU - Ohkura, Naganari
AU  - Ohkura N
FAU - Takahashi, Maho
AU  - Takahashi M
FAU - Nagamura, Yuko
AU  - Nagamura Y
FAU - Kitabayashi, Issay
AU  - Kitabayashi I
FAU - Tsukada, Toshihiko
AU  - Tsukada T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Amino Acids)
RN  - 0 (Chromatin)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Peptides)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Ubiquitin)
RN  - 63231-63-0 (RNA)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Amino Acids/chemistry
MH  - Animals
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - COS Cells
MH  - Cell Line
MH  - Chromatin/metabolism
MH  - Cysteine Endopeptidases/*metabolism
MH  - Genes, Tumor Suppressor
MH  - HSP70 Heat-Shock Proteins/metabolism
MH  - Humans
MH  - Mass Spectrometry
MH  - Mice
MH  - Microscopy, Fluorescence
MH  - Multienzyme Complexes/*metabolism
MH  - Multiple Endocrine Neoplasia Type 1/*genetics
MH  - Mutation
MH  - *Mutation, Missense
MH  - Peptides/chemistry
MH  - Plasmids/metabolism
MH  - Polymorphism, Genetic
MH  - Precipitin Tests
MH  - Proteasome Endopeptidase Complex
MH  - Proto-Oncogene Proteins/*genetics
MH  - RNA/metabolism
MH  - Time Factors
MH  - Transfection
MH  - Ubiquitin/*metabolism
PMC - PMC444842
EDAT- 2004/07/16 05:00
MHDA- 2004/08/18 05:00
PMCR- 2004/08/01
CRDT- 2004/07/16 05:00
PHST- 2004/07/16 05:00 [pubmed]
PHST- 2004/08/18 05:00 [medline]
PHST- 2004/07/16 05:00 [entrez]
PHST- 2004/08/01 00:00 [pmc-release]
AID - 24/15/6569 [pii]
AID - 0091-04 [pii]
AID - 10.1128/MCB.24.15.6569-6580.2004 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2004 Aug;24(15):6569-80. doi: 10.1128/MCB.24.15.6569-6580.2004.