PMID- 14516745
OWN - NLM
STAT- MEDLINE
DCOM- 20031105
LR  - 20190710
IS  - 0022-2836 (Print)
IS  - 0022-2836 (Linking)
VI  - 333
IP  - 1
DP  - 2003 Oct 10
TI  - Functional characterization of a promoter region in the human MEN1 tumor 
      suppressor gene.
PG  - 87-102
AB  - Our previous studies on the human MEN1 (multiple endocrine neoplasia type 1) gene 
      revealed heterogeneity of MEN1 2.8 kb transcripts related to variation in their 
      5' UTR only. Six distinct exons 1 (e1A-e1F) were isolated that suggested the 
      existence of multiple but not already identified transcriptional start sites 
      (TSS) and of a complex transcriptional control. Identification of a minimal 
      promoter region and its adjacent regulatory regions appears an inescapable step 
      to the understanding of MEN1 gene transcriptional regulation in normal and 
      pathological situations. For this purpose, we subcloned the approximately 2000 bp 
      region situated directly upstream of the exon 2 in front of a luciferase reporter 
      gene, and we analyzed functional consequences of 5' and 3' serial deletions, 
      comparatively in a series of endocrine versus non-endocrine cell lines. Primer 
      extension and RPA experiments demonstrate that in HEK293 cells transcription 
      initiated simultaneously at several points in endogenous MEN1 promoter as well as 
      in transfected promoter fragments in reporter plasmids, mainly in Inr elements 
      that are efficiently employed to synthetize previously described exons e1A-e1D. 
      Functional consequences of TSS deletion are directly related to cellular context. 
      The minimal promoter region is localized between -135 and -36. Five large 
      adjacent cis-regulatory regions (UR1-UR5) exist upstream of this minimal promoter 
      region, whose activity depend not only on the cellular context but also on the 
      presence of a downstream sequence DR1. Five small cis-regulatory elements (C1-C5) 
      are localized between -325 and -107. Overexpression of exogenous menin, the MEN1 
      gene's product, in mouse embryonic fibroblasts from Men1(-/-) knock-out mice 
      dose-dependently decreases MEN1 promoter activity, through sequences surrounding 
      the minimal promoter. Our data highlight the existence of a complex 
      transcriptional regulation of the MEN1 gene, whose activity is clearly modulated 
      depending not only on the cellular context but also on menin intracellular 
      levels. They are the molecular bases required for a future understanding of a 
      potential specific transcription control in endocrine cells.
FAU - Fromaget, Maud
AU  - Fromaget M
AD  - INSERM U45, Systeme neuroendocrine et epithelium normal et neoplasique, IFR 
      Laennec, Lyon, France.
FAU - Vercherat, Cecile
AU  - Vercherat C
FAU - Zhang, Chang X
AU  - Zhang CX
FAU - Zablewska, Barbara
AU  - Zablewska B
FAU - Gaudray, Patrick
AU  - Gaudray P
FAU - Chayvialle, Jean-Alain
AU  - Chayvialle JA
FAU - Calender, Alain
AU  - Calender A
FAU - Cordier-Bussat, Martine
AU  - Cordier-Bussat M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Mol Biol
JT  - Journal of molecular biology
JID - 2985088R
RN  - 0 (MEN1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Base Sequence
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Molecular Sequence Data
MH  - Neoplasm Proteins/*genetics
MH  - *Promoter Regions, Genetic
MH  - *Proto-Oncogene Proteins
MH  - Sequence Analysis, DNA
MH  - Sequence Deletion
EDAT- 2003/10/01 05:00
MHDA- 2003/11/06 05:00
CRDT- 2003/10/01 05:00
PHST- 2003/10/01 05:00 [pubmed]
PHST- 2003/11/06 05:00 [medline]
PHST- 2003/10/01 05:00 [entrez]
AID - S0022283603010040 [pii]
AID - 10.1016/j.jmb.2003.08.001 [doi]
PST - ppublish
SO  - J Mol Biol. 2003 Oct 10;333(1):87-102. doi: 10.1016/j.jmb.2003.08.001.