title: MEN1 missense mutations impair sensitization to apoptosis induced by wild-type menin in endocrine pancreatic tumor cells.
abstract: OBJECTIVE
  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.
authors.affiliation: INSERM, U865, IFR 62, Lyon, France.
authors.forename: Wissam
authors.initials: W
authors.lastname: Bazzi
authors.forename: Maud
authors.initials: M
authors.lastname: Renon
authors.forename: Cécile
authors.initials: C
authors.lastname: Vercherat
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Hamze
authors.forename: Annie
authors.initials: A
authors.lastname: Lacheretz-Bernigaud
authors.forename: Hayian
authors.initials: H
authors.lastname: Wang
authors.forename: Martine
authors.initials: M
authors.lastname: Blanc
authors.forename: Colette
authors.initials: C
authors.lastname: Roche
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Chayvialle
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000235:genetics*; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins