PMID- 22275377
OWN - NLM
STAT- MEDLINE
DCOM- 20120501
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 11
DP  - 2012 Mar 9
TI  - Impaired transforming growth factor-beta (TGF-beta) transcriptional activity and cell 
      proliferation control of a menin in-frame deletion mutant associated with 
      multiple endocrine neoplasia type 1 (MEN1).
PG  - 8584-97
LID - 10.1074/jbc.M112.341958 [doi]
AB  - Multiple endocrine neoplasia type 1 (MEN1) is characterized by tumors of the 
      parathyroid, enteropancreas, and anterior pituitary. The MEN1 gene encodes the 
      tumor suppressor menin of 610 amino acids that has multiple protein partners and 
      activities. The particular pathways that, when lost, lead to tumorigenesis are 
      not known. We demonstrated that members of a three-generation MEN1 kindred are 
      heterozygous for a donor splice site mutation at the beginning of intron 3 (IVS3 
      + 1G-->A). Lymphoblastoid cells of a mutant gene carrier had, in addition to the 
      wild-type menin transcript, an aberrant transcript resulting from use of a 
      cryptic splice site within exon III that splices to the start of exon IV. The 
      predicted menin Delta(184-218) mutant has an in-frame deletion of 35 amino acids but 
      is otherwise of wild-type sequence. The transfected menin Delta(184-218) mutant was 
      well expressed and fully able to mediate the normal inhibition of the activity of 
      the transcriptional regulators JunD and NF-kappaB. However, it was defective in 
      mediating TGF-beta-stimulated Smad3 action in promoter-reporter assays in insulinoma 
      cells. Importantly, lymphoblastoid cells from an individual heterozygous for the 
      mutation had reduced TGF-beta-induced (Smad3) transcriptional activity but normal 
      JunD and NF-kappaB function. In addition, the mutant gene carrier lymphoblastoid 
      cells proliferated faster and were less responsive to the cytostatic effects of 
      TGF-beta than cells from an unaffected family member. In conclusion, the menin 
      mutant exhibits selective loss of the TGF-beta signaling pathway and loss of cell 
      proliferation control contributing to the development of MEN1.
FAU - Canaff, Lucie
AU  - Canaff L
AD  - Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, 
      Quebec H3A 1A1, Canada.
FAU - Vanbellinghen, Jean-Francois
AU  - Vanbellinghen JF
FAU - Kaji, Hiroshi
AU  - Kaji H
FAU - Goltzman, David
AU  - Goltzman D
FAU - Hendy, Geoffrey N
AU  - Hendy GN
LA  - eng
GR  - MOP-86703/Canadian Institutes of Health Research/Canada
GR  - MOP-9315/Canadian Institutes of Health Research/Canada
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120124
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (JunD protein, human)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (RNA Splice Sites)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad3 Protein)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged, 80 and over
MH  - Amino Acid Sequence/*genetics
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Female
MH  - Humans
MH  - Introns
MH  - Male
MH  - Middle Aged
MH  - Multiple Endocrine Neoplasia Type 1/genetics/*metabolism/pathology
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-jun/genetics/metabolism
MH  - RNA Splice Sites/*genetics
MH  - Rats
MH  - *Sequence Deletion
MH  - *Signal Transduction
MH  - Smad3 Protein/genetics/metabolism
MH  - Transforming Growth Factor beta/genetics/*metabolism
PMC - PMC3318699
EDAT- 2012/01/26 06:00
MHDA- 2012/05/02 06:00
PMCR- 2013/03/09
CRDT- 2012/01/26 06:00
PHST- 2012/01/26 06:00 [entrez]
PHST- 2012/01/26 06:00 [pubmed]
PHST- 2012/05/02 06:00 [medline]
PHST- 2013/03/09 00:00 [pmc-release]
AID - S0021-9258(20)61003-1 [pii]
AID - M112.341958 [pii]
AID - 10.1074/jbc.M112.341958 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Mar 9;287(11):8584-97. doi: 10.1074/jbc.M112.341958. Epub 2012 
      Jan 24.