![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
/VP16 Hybrid Factor Activates Expression of the Human B-Type Natriuretic Peptide GeneGenzyme Corporation, Framingham, Massachusetts
Hypoxia-inducible factor-1 (HIF-1) is a primary regulator of the physiological response to hypoxia. A recombinant adenovirus expressing a constitutively active hybrid form of the HIF-1
subunit (Ad2/HIF-1/VP16) is being evaluated as a gene therapy for the treatment of peripheral vascular disease. Ad2/HIF-1/VP16 up-regulates known HIF-1-responsive genes, including those involved in angiogenesis. Expression profile analysis revealed that the brain natriuretic peptide (BNP) gene was significantly up-regulated in response to HIF-1/VP16 in human fetal cardiac cells. Real-time reverse transcription-polymerase chain reaction analyses confirmed transcriptional activation of the BNP gene by HIF-1/VP16 in human but not rat cardiac cells. Because hypoxia itself did not increase human BNP gene expression in these analyses, the mechanism of the HIF-1/VP16 effect was determined. Analyses of promoter deletion mutants suggested that the cis-acting sequence in the human BNP promoter mediating activation by HIF-1/VP16 was a putative HIF-1 responsive element (HRE) located at -466. An SV40 basal promoter-luciferase plasmid containing a minimal BNP HRE was up-regulated by HIF-1/VP16, whereas a similar construct carrying a mutation within the HIF-1 binding site was not. Mutation of an E-box motif within the BNP HRE reduced HIF-1/VP16-mediated transcriptional activation by 50%. Gel-shift analyses showed that both the native HIF-1 and HIF-1/VP16 are able to bind to a probe containing the HIF-1 binding site. These experiments demonstrate the existence of a functional HRE in the BNP promoter and further define the scope and mechanism of action of Ad2/HIF-1/VP16.
Address correspondence to: Dr. Karen A. Vincent, Genzyme Corporation, 31 New York Ave, P.O. Box 9322, Framingham, MA 01701-9322. E-mail: karen.vincent{at}genzyme.com
Related articles in MolPharm:
(HIF-1)/VP16 Enhances B-Type Natriuretic Peptide Gene Expression via a HIF-1-Responsive Element
This article has been cited by other articles:
|
|
 |
|
  R. Due-Andersen, U. Pedersen-Bjergaard, T. Hoi-Hansen, N. V. Olsen, C. Kistorp, J. Faber, F. Boomsma, and B. Thorsteinsson NT-pro-BNP during hypoglycemia and hypoxemia in normal subjects: impact of renin-angiotensin system activity J Appl Physiol, April 1, 2008; 104(4): 1080 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Khan, M. Birbach, M. S. Cohen, R. F. Ittenbach, T. L. Spray, R. J. Levy, and J. W. Gaynor Chronic Hypoxemia Increases Ventricular Brain Natriuretic Peptide Precursors in Neonatal Swine Ann. Thorac. Surg., February 1, 2008; 85(2): 618 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nybo, M. Benn, R. Mogelvang, J. S. Jensen, P. Schnohr, J. F. Rehfeld, and J. P. Goetze Impact of Hemoglobin on Plasma Pro-B-Type Natriuretic Peptide Concentrations in the General Population Clin. Chem., November 1, 2007; 53(11): 1921 - 1927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Wilhide and W. K. Jones Potential Therapeutic Gene for the Treatment of Ischemic Disease: Ad2/Hypoxia-Inducible Factor-1{alpha} (HIF-1)/VP16 Enhances B-Type Natriuretic Peptide Gene Expression via a HIF-1-Responsive Element Mol. Pharmacol., June 1, 2006; 69(6): 1773 - 1778. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
