PMID- 22708734
OWN - NLM
STAT- MEDLINE
DCOM- 20130117
LR  - 20220408
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 12
DP  - 2012 Jun 18
TI  - Menin and p53 have non-synergistic effects on tumorigenesis in mice.
PG  - 252
LID - 10.1186/1471-2407-12-252 [doi]
AB  - BACKGROUND: While it is now more than a decade since the first description of the 
      gene mutation underlying the tumour predisposition syndrome multiple endocrine 
      neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to 
      prevent development of tumours is still poorly understood. METHODS: We undertook 
      a genetic experiment to assess whether menin synergises with p53. Mice carrying 
      various combinations of Men1 and Trp53 mutations were generated then survival and 
      pathology assessed. RESULTS: While homozygous loss of Trp53 in mice resulted in 
      early onset, aggressive tumours and profoundly reduced lifespan, heterozygous 
      loss of either Trp53 or Men1 caused later onset disease, with a spectrum of 
      tumours characteristic of each tumour suppressor gene. Loss of one copy of Men1 
      in animals also lacking both alleles of Trp53 did not exacerbate phenotype, based 
      on survival, animal weight or sites of pathology, compared to Trp53 deletion 
      alone. Dual heterozygous deletion of Men1 and Trp53 resulted in a small reduction 
      in lifespan compared to the individual mutations, without new tumour sites. In 
      the adrenal, we observed development of cortical tumours in dual heterozygous 
      animals, as we have previously seen in Men1+/- animals, and there was loss of 
      heterozygosity at the Men1 allele in these tumours. Median number of pathology 
      observations per animal was increased in dual heterozygous animals compared with 
      heterozygous loss of Trp53 alone. CONCLUSIONS: Simultaneous heterozygous deletion 
      of Men1 in animals with either heterozygous or homozygous deletion of Trp53 did 
      not result in formation of tumours at any new sites, implying additive rather 
      than synergistic effects of these pathways. Mice that were Men1+/- in addition to 
      Trp53+/- had tumours in endocrine as well as other sites, implying that increase 
      in total tumour burden, at sites typically associated with either Men1 or Trp53 
      loss, contributed to the slight decrease in survival in Men1+/-: Trp53+/- animals 
      in comparison with their littermates.
FAU - Loffler, Kelly A
AU  - Loffler KA
AD  - Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD, 4006, 
      Australia. kelly.loffler@qimr.edu.au
FAU - Mould, Arne W
AU  - Mould AW
FAU - Waring, Paul M
AU  - Waring PM
FAU - Hayward, Nicholas K
AU  - Hayward NK
FAU - Kay, Graham F
AU  - Kay GF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120618
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Adrenal Glands/metabolism/pathology
MH  - Animals
MH  - Body Weight
MH  - Cell Transformation, Neoplastic/*genetics/metabolism
MH  - Genotype
MH  - Mice
MH  - Mice, Knockout
MH  - Multiple Endocrine Neoplasia Type 1/*genetics/metabolism
MH  - Mutation
MH  - Neoplasms/genetics/mortality/pathology
MH  - Pancreas/metabolism/pathology
MH  - Tumor Suppressor Protein p53/*genetics/metabolism
PMC - PMC3433377
EDAT- 2012/06/20 06:00
MHDA- 2013/01/18 06:00
PMCR- 2012/06/18
CRDT- 2012/06/20 06:00
PHST- 2011/12/01 00:00 [received]
PHST- 2012/06/18 00:00 [accepted]
PHST- 2012/06/20 06:00 [entrez]
PHST- 2012/06/20 06:00 [pubmed]
PHST- 2013/01/18 06:00 [medline]
PHST- 2012/06/18 00:00 [pmc-release]
AID - 1471-2407-12-252 [pii]
AID - 10.1186/1471-2407-12-252 [doi]
PST - epublish
SO  - BMC Cancer. 2012 Jun 18;12:252. doi: 10.1186/1471-2407-12-252.