PMID- 22086850
OWN - NLM
STAT- MEDLINE
DCOM- 20120409
LR  - 20211021
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 72
IP  - 2
DP  - 2012 Jan 15
TI  - Regulation of matrix metalloproteinase genes by E2F transcription factors: 
      Rb-Raf-1 interaction as a novel target for metastatic disease.
PG  - 516-26
LID - 10.1158/0008-5472.CAN-11-2647 [doi]
AB  - The retinoblastoma (Rb)-E2F transcriptional regulatory pathway plays a major role 
      in cell-cycle regulation, but its role in invasion and metastasis is less well 
      understood. We find that many genes involved in the invasion of cancer cells, 
      such as matrix metalloproteinases (MMP), have potential E2F-binding sites in 
      their promoters. E2F-binding sites were predicted on all 23 human MMP gene 
      promoters, many of which harbored multiple E2F-binding sites. Studies presented 
      here show that MMP genes such as MMP9, MMP14, and MMP15 which are overexpressed 
      in non-small cell lung cancer, have multiple E2F-binding sites and are regulated 
      by the Rb-E2F pathway. Chromatin immunoprecipitation assays showed the 
      association of E2F1 with the MMP9, MMP14, and MMP15 promoters, and transient 
      transfection experiments showed that these promoters are E2F responsive. 
      Correspondingly, depletion of E2F family members by RNA interference techniques 
      reduced the expression of these genes with a corresponding reduction in collagen 
      degradation activity. Furthermore, activating Rb by inhibiting the interaction of 
      Raf-1 with Rb by using the Rb-Raf-1 disruptor RRD-251 was sufficient to inhibit 
      MMP transcription. This led to reduced invasion and migration of cancer cells in 
      vitro and metastatic foci development in a tail vein lung metastasis model in 
      mice. These results suggest that E2F transcription factors may play a role in 
      promoting metastasis through regulation of MMP genes and that targeting the 
      Rb-Raf-1 interaction is a promising approach for the treatment of metastatic 
      disease.
FAU - Johnson, Jackie L
AU  - Johnson JL
AD  - Department of Tumor Biology, University of South Florida, Tampa, Florida, USA.
FAU - Pillai, Smitha
AU  - Pillai S
FAU - Pernazza, Danielle
AU  - Pernazza D
FAU - Sebti, Said M
AU  - Sebti SM
FAU - Lawrence, Nicholas J
AU  - Lawrence NJ
FAU - Chellappan, Srikumar P
AU  - Chellappan SP
LA  - eng
GR  - P01 CA118210/CA/NCI NIH HHS/United States
GR  - P01 CA118210-05/CA/NCI NIH HHS/United States
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - CA118120/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111115
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (E2F Transcription Factors)
RN  - 0 (Phosphatidylethanolamine Binding Protein)
RN  - 0 (Retinoblastoma Protein)
RN  - 9000-70-8 (Gelatin)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
EIN - Cancer Res. 2012 Mar 1;72(5):1317
MH  - Animals
MH  - Breast Neoplasms/genetics/metabolism/pathology
MH  - Carcinoma, Non-Small-Cell Lung/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - E2F Transcription Factors/*genetics/metabolism
MH  - Enzyme Assays/methods
MH  - Female
MH  - Gelatin/metabolism
MH  - *Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Lung Neoplasms/genetics/metabolism/pathology
MH  - Matrix Metalloproteinases/biosynthesis/*genetics/metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Neoplasm Metastasis
MH  - Phosphatidylethanolamine Binding Protein/*metabolism
MH  - Retinoblastoma Protein/genetics/*metabolism
MH  - Transcription, Genetic
MH  - Transfection
PMC - PMC3261351
MID - NIHMS339355
EDAT- 2011/11/17 06:00
MHDA- 2012/04/10 06:00
PMCR- 2013/01/15
CRDT- 2011/11/17 06:00
PHST- 2011/11/17 06:00 [entrez]
PHST- 2011/11/17 06:00 [pubmed]
PHST- 2012/04/10 06:00 [medline]
PHST- 2013/01/15 00:00 [pmc-release]
AID - 0008-5472.CAN-11-2647 [pii]
AID - 10.1158/0008-5472.CAN-11-2647 [doi]
PST - ppublish
SO  - Cancer Res. 2012 Jan 15;72(2):516-26. doi: 10.1158/0008-5472.CAN-11-2647. Epub 
      2011 Nov 15.