PMID- 15867378
OWN - NLM
STAT- MEDLINE
DCOM- 20050615
LR  - 20081121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 9
DP  - 2005 May 1
TI  - Impairment of stromelysin-1 transcriptional activity by promoter mutations in 
      high microsatellite instability colorectal tumors.
PG  - 3811-4
AB  - Colorectal tumorigenesis is characterized by the sequential inactivation of a 
      series of tumor suppressor genes (microsatellite-stable tumors) and genetic or 
      epigenetic alterations in mismatch repair genes in nonpoliposic hereditary 
      tumours and 13% to 15% of sporadic colorectal cancer [high microsatellite 
      instability (MSI-H) tumors]. We hypothesized a molecular mechanism for MSI-H 
      colorectal tumors related to matrix metalloproteinase 3 (MMP-3) promoter 
      mutations, down-regulation of MMP-3 expression, and impairment of MMP-9 
      activation. We have now analyzed the 2.2-kb full MMP-3 promoter to assess the 
      mutation distribution. The mutations found are restricted to the polymorphic 
      region that includes the zinc-binding protein (ZBP-89) binding element. To show 
      that these alterations were the cause of the low expression of this gene, we have 
      generated three constructs with different MMP-3 promoters (wild type and two 
      mutants) and we have expressed them in SW480 human colorectal cells. The basal 
      transcriptional activity of wild-type MMP-3 promoter was much higher than the 
      mutants activity. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced 
      transcriptional activity of wild-type MMP-3 promoter was 10-fold higher than the 
      mutants activity. Dexamethasone inhibited the basal transcriptional activity of 
      wild-type MMP-3 promoter and of the two mutants found in the MSI-H subgroup of 
      colorectal tumors. Significantly, dexamethasone almost completely blunted the 
      TPA-induced effect on wild-type MMP-3 promoter transcriptional activity and on 
      the mutants, even below their basal activity. Our data show that mutations found 
      in the polymorphic region of the MMP-3 promoter from MSI-H colorectal tumors 
      impair its basal and induced transcriptional activity, which may contribute to 
      their better clinical outcome.
FAU - Moran, Alberto
AU  - Moran A
AD  - Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, 
      Universidad Complutense, Madrid, Spain.
FAU - Iniesta, Pilar
AU  - Iniesta P
FAU - de Juan, Carmen
AU  - de Juan C
FAU - Garcia-Aranda, Cristina
AU  - Garcia-Aranda C
FAU - Diaz-Lopez, Antonio
AU  - Diaz-Lopez A
FAU - Benito, Manuel
AU  - Benito M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (ZNF148 protein, human)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Base Sequence
MH  - Colorectal Neoplasms/*enzymology/*genetics
MH  - DNA-Binding Proteins/genetics
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Transfer Techniques
MH  - Humans
MH  - Matrix Metalloproteinase 3/biosynthesis/*genetics
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Microsatellite Repeats/genetics
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Plasmids/genetics
MH  - Promoter Regions, Genetic/genetics
MH  - Transcription Factors/genetics
MH  - Transcriptional Activation/*genetics
EDAT- 2005/05/04 09:00
MHDA- 2005/06/16 09:00
CRDT- 2005/05/04 09:00
PHST- 2005/05/04 09:00 [pubmed]
PHST- 2005/06/16 09:00 [medline]
PHST- 2005/05/04 09:00 [entrez]
AID - 65/9/3811 [pii]
AID - 10.1158/0008-5472.CAN-04-4442 [doi]
PST - ppublish
SO  - Cancer Res. 2005 May 1;65(9):3811-4. doi: 10.1158/0008-5472.CAN-04-4442.