PMID- 18199540
OWN - NLM
STAT- MEDLINE
DCOM- 20080214
LR  - 20161124
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 2
DP  - 2008 Jan 15
TI  - Regulation of vascular endothelial growth factor D by orphan receptors hepatocyte 
      nuclear factor-4 alpha and chicken ovalbumin upstream promoter transcription 
      factors 1 and 2.
PG  - 457-66
LID - 10.1158/0008-5472.CAN-07-5136 [doi]
AB  - Vascular endothelial growth factor D has recently been linked to the control of 
      lymphangiogenesis and lymphatic metastasis. The molecular determinants regulating 
      vegf-D gene transcription, however, have not yet been identified. After isolation 
      of 2 kb of 5'-flanking DNA of the human vegf-D gene, we identified a novel, 
      atypical direct repeat (DR) element consisting of a consensus half-site (AGGTCA) 
      at -125/-119 and a degenerated DR half-site (ATGTTA) at -99/-94 as sufficient and 
      necessary for vegf-D transcription. The vegf-D DR element is bound and activated 
      by the orphan receptors hepatocyte nuclear factor 4 alpha (HNF-4 alpha) and 
      chicken ovalbumin upstream promoter transcription factor (COUP-TF)-1/COUP-TF2. 
      Additionally, chromatin immunoprecipitation assays identified transcriptional 
      coactivators cyclic AMP-responsive element binding protein-binding protein and 
      glucocorticoid receptor interacting protein 1 at the vegf-D DR element and 
      functional assays confirmed their stimulatory effect on the vegf-D promoter. 
      Histone deacetylase inhibition by trichostatin A led to accumulation of 
      acetylated histones H3/H4 at the vegf-D promoter, up-regulation of vegf-D mRNA 
      levels, and transactivation of vegf-D promoter reporter gene constructs in cancer 
      cell lines. This study for the first time describes the molecular determinants in 
      cis and trans controlling vegf-D gene transcription and identifies interaction of 
      HNF-4 alpha and COUP-TF1/COUP-TF2 with a proximal, atypical DR element as 
      indispensable for vegf-D transcription. Moreover, our findings suggest that 
      epigenetic control of histone acetylation represents an important determinant of 
      vegf-D gene expression in cancer cells. These results provide novel insights into 
      the molecular machinery controlling vegf-D gene expression and may add to a 
      better understanding of the regulation of lymphangiogenesis in vascular 
      development and cancer.
FAU - Schafer, Georgia
AU  - Schafer G
AD  - Laboratory for Angiogenesis and Tumor Metastasis, Charite University Hospital, 
      Berlin, Germany.
FAU - Wissmann, Christoph
AU  - Wissmann C
FAU - Hertel, Johannes
AU  - Hertel J
FAU - Lunyak, Victoria
AU  - Lunyak V
FAU - Hocker, Michael
AU  - Hocker M
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (COUP Transcription Factor I)
RN  - 0 (COUP Transcription Factor II)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Histones)
RN  - 0 (NCOA2 protein, human)
RN  - 0 (Nuclear Receptor Coactivator 2)
RN  - 0 (Trans-Activators)
RN  - 0 (Vascular Endothelial Growth Factor D)
RN  - EC 2.3.1.48 (CREB-Binding Protein)
RN  - EC 2.3.1.48 (CREBBP protein, human)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
SB  - IM
MH  - Acetylation
MH  - Base Sequence
MH  - COUP Transcription Factor I/metabolism/*physiology
MH  - COUP Transcription Factor II/metabolism/*physiology
MH  - CREB-Binding Protein/metabolism/physiology
MH  - *Gene Expression Regulation
MH  - Hepatocyte Nuclear Factor 4/metabolism/*physiology
MH  - Histone Acetyltransferases/metabolism
MH  - Histones/metabolism
MH  - Humans
MH  - Molecular Sequence Data
MH  - Nuclear Receptor Coactivator 2/metabolism/physiology
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - Trans-Activators/metabolism/physiology
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor D/*genetics
EDAT- 2008/01/18 09:00
MHDA- 2008/02/15 09:00
CRDT- 2008/01/18 09:00
PHST- 2008/01/18 09:00 [pubmed]
PHST- 2008/02/15 09:00 [medline]
PHST- 2008/01/18 09:00 [entrez]
AID - 68/2/457 [pii]
AID - 10.1158/0008-5472.CAN-07-5136 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Jan 15;68(2):457-66. doi: 10.1158/0008-5472.CAN-07-5136.