PMID- 18775714
OWN - NLM
STAT- MEDLINE
DCOM- 20081125
LR  - 20081110
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 135
IP  - 5
DP  - 2008 Nov
TI  - MEN1 missense mutations impair sensitization to apoptosis induced by wild-type 
      menin in endocrine pancreatic tumor cells.
PG  - 1698-1709.e2
LID - 10.1053/j.gastro.2008.07.031 [doi]
AB  - BACKGROUND & AIMS: Missense mutations account for 30% of mutations identified in 
      patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome. They raise 
      several issues: the distinction between pathogenic mutations and polymorphisms is 
      sometimes difficult and the functional effects of missense mutations are unclear. 
      We aimed to evaluate the functional consequences of missense MEN1 mutations in an 
      appropriate endocrine cellular context. METHODS: From the INS-1 insulinoma cell 
      line, we established clones conditionally over expressing wild-type (WT) menin or 
      its A160T, H317Y, and A541T variants. We compared the consequences of WT or 
      variant menin over expression on apoptotic response after gamma-irradiation and 
      analyzed the interactions of these proteins with p53. RESULTS: WT menin over 
      expression sensitized INS-r3 cells to apoptosis through amplification of 
      caspase-3 activation, increased p53 acetylation, and accelerated p21 activation; 
      moreover, over expressed WT menin could be recovered in p53-containing complexes. 
      For all 3 missense mutations tested, the functional effects observed with WT were 
      impaired significantly and only low amounts of variant menin proteins were 
      recovered in p53-containing complexes. CONCLUSIONS: Taking advantage of a new 
      endocrine cellular model, we show a loss of function for 2 missense 
      disease-related menin mutants and for a controversial variant as well. 
      Furthermore, our results suggest the existence of functional interactions between 
      p53 and menin for the control of apoptosis, which may cast new light on the 
      mechanisms of endocrine tumorigenesis.
FAU - Bazzi, Wissam
AU  - Bazzi W
AD  - INSERM, U865, IFR 62, Lyon, France.
FAU - Renon, Maud
AU  - Renon M
FAU - Vercherat, Cecile
AU  - Vercherat C
FAU - Hamze, Zeinab
AU  - Hamze Z
FAU - Lacheretz-Bernigaud, Annie
AU  - Lacheretz-Bernigaud A
FAU - Wang, Hayian
AU  - Wang H
FAU - Blanc, Martine
AU  - Blanc M
FAU - Roche, Colette
AU  - Roche C
FAU - Calender, Alain
AU  - Calender A
FAU - Chayvialle, Jean-Alain
AU  - Chayvialle JA
FAU - Scoazec, Jean-Yves
AU  - Scoazec JY
FAU - Cordier-Bussat, Martine
AU  - Cordier-Bussat M
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080731
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (DNA, Neoplasm)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Cell Count
MH  - Cell Proliferation
MH  - DNA, Neoplasm/*genetics
MH  - Fluorescent Antibody Technique, Indirect
MH  - Gene Expression Regulation, Neoplastic
MH  - Genes, p53/genetics
MH  - Humans
MH  - Immunoblotting
MH  - Multiple Endocrine Neoplasia Type 1/*genetics/metabolism/pathology
MH  - *Mutation, Missense
MH  - Pancreatic Neoplasms/*genetics/metabolism/pathology
MH  - Polymerase Chain Reaction
MH  - Proto-Oncogene Proteins/*genetics/metabolism
MH  - Tumor Cells, Cultured
EDAT- 2008/09/09 09:00
MHDA- 2008/12/17 09:00
CRDT- 2008/09/09 09:00
PHST- 2007/12/22 00:00 [received]
PHST- 2008/06/27 00:00 [revised]
PHST- 2008/07/24 00:00 [accepted]
PHST- 2008/09/09 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/09/09 09:00 [entrez]
AID - S0016-5085(08)01403-0 [pii]
AID - 10.1053/j.gastro.2008.07.031 [doi]
PST - ppublish
SO  - Gastroenterology. 2008 Nov;135(5):1698-1709.e2. doi: 
      10.1053/j.gastro.2008.07.031. Epub 2008 Jul 31.