ErbB2 overexpression in mammary cells upregulates VEGF through the core promoter.
The angiogenic molecule, vascular endothelial growth factor (VEGF), is a critical regulator of normal and pathologic angiogenesis. ErbB2, an epidermal growth factor receptor family member whose overexpression in mammary tumors is correlated with poor patient prognosis, has been implicated as a positive modulator of VEGF expression. Mammary tumor cells overexpressing ErbB2 (NAFA cells) and a normal mouse mammary cell line (HC11) transfected with ErbB2 expression vectors were used to study the effects of ErbB2 overexpression on VEGF regulation. We found that ErbB2 overexpression led to an increase in endogenous VEGF mRNA as well as ErbB3 protein levels in HC11 cells. Additionally, we determined that ErbB2 overexpression-mediated upregulation of VEGF involves at least two distinct promoter elements, one previously identified as the hypoxia responsive element and the other the core promoter region (-161 to -51bp), which is specifically controlled via two adjacent SP1 binding sites (-80 to -60bp).
Loureiro
Robyn M B
RM
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA.
Maharaj
Arindel S R
AS
Dankort
David
D
Muller
William J
WJ
D'Amore
Patricia A
PA
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D020890:Neuregulin-1 / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020890:Neuregulin-1; D020033:Protein Isoforms; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D042461:Vascular Endothelial Growth Factor A; C087230:heregulin beta1