Skip Navigation



Carcinogenesis Advance Access published online on April 1, 2008
Carcinogenesis, doi:10.1093/carcin/bgn088
This Article
Right arrow Advance Access manuscript (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Salnikow, K.
Right arrow Articles by Niederhuber, J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Salnikow, K.
Right arrow Articles by Niederhuber, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published by Oxford University Press 2008.

Regulation of Hypoxia-inducible Genes by ETS1 Transcription Factor

Konstantin Salnikow1,*, Olga Aprelikova2, Sergey Ivanov3, Sean Tackett2, Monika Kaczmarek1, Aldona Karaczyn1, Herman Yee3, Kazimierz S. Kasprzak1 and John Niederhuber2

1 Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland, 21702
2 Laboratory of Tumor and Stem Cell Biology, National Cancer Institute, Bethesda, Maryland, 20892
3 New York University School of Medicine, New York, New York, 10016

* Corresponding author: Konstantin Salnikow, Ph.D., National Cancer Institute at Frederick, Bldg. 538, Room 205 E Frederick, MD 21702, Phone: 301-846-5623, Fax: 301-846-5946, E-mail: salnikow{at}ncifcrf.gov

HIF-1 regulates the expression of genes that facilitate tumor cell survival by making them more resistant to therapeutic intervention. Recent evidence suggests that the activation of other transcription factors, in cooperation with HIF-1 or acting alone, is involved in the up-regulation of hypoxia-inducible genes. Here we report that high cell density, a condition that might mimic the physiologic situation in growing tumor and most likely representing nutritional starvation, up-regulates hypoxia-inducible genes. This up-regulation can occur in HIF-independent manner since hypoxia-inducible genes CA9, LOXL2, and NDRG1/Cap43 can be up-regulated by increased cell density under both normoxic and hypoxic conditions in both HIF-1{alpha}-proficient and -deficient mouse fibroblasts. Moreover, cell density up-regulates the same genes in 1HAEo- and A549 human lung epithelial cells. Searching for other transcription factors involved in the regulation of hypoxia-inducible genes by cell density we focused our attention on ETS1. As reported previously, members of ETS family transcription factors participate in the up-regulation of hypoxia-inducible genes. Here we provide evidence that ETS1 protein is up-regulated at high cell density in both human and mouse cells. The involvement of ETS1 in up-regulation of hypoxia-inducible genes was further confirmed in a luciferase reporter assay using co-transfection of ETS1 expression vector with NDRG1/Cap43 promoter construct. The down-regulation of ETS1 expression with siRNA inhibited the up-regulation of CA9 and NDRG1/Cap43 caused by increased cell density. Collectively, our data indicate the involvement of ETS1 along with HIF-1 in regulating hypoxia-inducible genes.

Key Words: ascorbate • cell density • ETS1 • HIF-1 • hypoxia-inducible genes • carbonic anhydrase 9 • NDRG1/Cap43

Received November 15, 2007; revised February 25, 2008; accepted March 15, 2008.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.