| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
Stabilization
Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic [S. K., M. K., A. C., S. P., J. P.]; British Columbia Cancer Research Centre and British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3 Canada [P. L. O.]; Laboratory of Immunobiology, National Cancer Institute, NIH, Bethesda, Maryland 20889 [M. I. L.]; and Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92717 [E. J. S.]
Transcription of the gene coding for the tumor-associated antigen MN/carbonicanhydrase IX (CAIX) is regulated by hypoxia-inducible factor 1 (HIF-1).Previous studies identified CAIX expression in areas adjacentto hypoxic regions in solid tumors and suggested supplementary/alternative modes of regulation. To better understand the mechanisms activating CAIX expression, we characterized the cell density-dependent induction of CAIX in HeLa cells. This process is anchorage and serum independent and is not mediated by a soluble factor, decreased pH, or lowered glucose concentration. Stabilization of HIF-1
was not observed in dense cultures. In contrast to sparse cell culture conditions, phosphatidylinositol 3'-kinase (PI3K) activity was significantly increased in dense HeLa cultures. The PI3K inhibitors LY294002 and wortmannin inhibited CAIX expression in dense cultures in a dose-dependent manner, specifically targeting the CA9 promoter (-173/+31 region) that was transactivated by constitutively active p110 PI3K subunit. The mechanism controlling CAIX expression in dense cultures is, however, dependent on lowered O2 tension because stirring abrogates induction of CAIX expression. Hypoxia- and cell density-induced CAIX expressions were mediated by two seemingly independent mechanisms, as documented by the additive effect of increased cell density and treatment with the hypoxia-mimic CoCl2 on levels of CAIX expression. The minimal cell density-dependent region within the CA9 promoter consists of the juxtaposed protected region 1 and hypoxia-response elements. However cell density-dependent CAIX expression was abrogated in the HIF-1
-deficient Kal3.5 cells, suggesting an important role of HIF-1 in the corresponding mechanism. Thus, induction of CAIX in high-density cultures requires separate but interdependent pathways of PI3K activation and a minimal level of HIF-1
. These interdependent pathways function at a lowered O2 concentration that is, however, above that necessary for HIF-1
stabilization.
This article has been cited by other articles:
![]() |
T. van den Beucken, M. Koritzinsky, H. Niessen, L. Dubois, K. Savelkouls, H. Mujcic, B. Jutten, J. Kopacek, S. Pastorekova, A. J. van der Kogel, et al. Hypoxia-induced Expression of Carbonic Anhydrase 9 Is Dependent on the Unfolded Protein Response J. Biol. Chem., September 4, 2009; 284(36): 24204 - 24212. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Salnikow, O. Aprelikova, S. Ivanov, S. Tackett, M. Kaczmarek, A. Karaczyn, H. Yee, K. S. Kasprzak, and J. Niederhuber Regulation of hypoxia-inducible genes by ETS1 transcription factor Carcinogenesis, August 1, 2008; 29(8): 1493 - 1499. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. A. Kazi and R. D. Koos Estrogen-Induced Activation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor Expression, and Edema in the Uterus Are Mediated by the Phosphatidylinositol 3-Kinase/Akt Pathway Endocrinology, May 1, 2007; 148(5): 2363 - 2374. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. J. Brennan, K. Jirstrom, A. Kronblad, R. C. Millikan, G. Landberg, M. J. Duffy, L. Ryden, W. M. Gallagher, and S. L. O'Brien CA IX is an Independent Prognostic Marker in Premenopausal Breast Cancer Patients with One to Three Positive Lymph Nodes and a Putative Marker of Radiation Resistance. Clin. Cancer Res., November 1, 2006; 12(21): 6421 - 6431. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Kaluz, M. Kaluzova, and E. J. Stanbridge Proteasomal Inhibition Attenuates Transcriptional Activity of Hypoxia-Inducible Factor 1 (HIF-1) via Specific Effect on the HIF-1{alpha} C-Terminal Activation Domain Mol. Cell. Biol., August 1, 2006; 26(15): 5895 - 5907. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Franco, S. Man, L. Chen, U. Emmenegger, Y. Shaked, A. M. Cheung, A. S. Brown, D. J. Hicklin, F. S. Foster, and R. S. Kerbel Targeted Anti-Vascular Endothelial Growth Factor Receptor-2 Therapy Leads to Short-term and Long-term Impairment of Vascular Function and Increase in Tumor Hypoxia. Cancer Res., April 1, 2006; 66(7): 3639 - 3648. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Mayer, M. Hockel, and P. Vaupel Carbonic Anhydrase IX Expression and Tumor Oxygenation Status Do Not Correlate at the Microregional Level in Locally Advanced Cancers of the Uterine Cervix Clin. Cancer Res., October 15, 2005; 11(20): 7220 - 7225. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Proescholdt, C. Mayer, M. Kubitza, T. Schubert, S.-Y. Liao, E. J. Stanbridge, S. Ivanov, E. H. Oldfield, A. Brawanski, and M. J. Merrill Expression of hypoxia-inducible carbonic anhydrases in brain tumors Neuro-oncol, October 1, 2005; 7(4): 465 - 475. [Abstract] [PDF] |
||||
![]() |
M M Vleugel, A E Greijer, A Shvarts, P van der Groep, M van Berkel, Y Aarbodem, H van Tinteren, A L Harris, P J van Diest, and E van der Wall Differential prognostic impact of hypoxia induced and diffuse HIF-1{alpha} expression in invasive breast cancer J. Clin. Pathol., February 1, 2005; 58(2): 172 - 177. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. M. Evans, K. D. Judy, I. Dunphy, W. T. Jenkins, W.-T. Hwang, P. T. Nelson, R. A. Lustig, K. Jenkins, D. P. Magarelli, S. M. Hahn, et al. Hypoxia Is Important in the Biology and Aggression of Human Glial Brain Tumors Clin. Cancer Res., December 15, 2004; 10(24): 8177 - 8184. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. J. Hutchison, H. R. Valentine, J. A. Loncaster, S. E. Davidson, R. D. Hunter, S. A. Roberts, A. L. Harris, I. J. Stratford, P. M. Price, and C. M. L. West Hypoxia-Inducible Factor 1{alpha} Expression as an Intrinsic Marker of Hypoxia: Correlation with Tumor Oxygen, Pimonidazole Measurements, and Outcome in Locally Advanced Carcinoma of the Cervix Clin. Cancer Res., December 15, 2004; 10(24): 8405 - 8412. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Bhattacharya, K. Toth, R. Mazurchuk, J. A. Spernyak, H. K. Slocum, L. Pendyala, R. Azrak, S. Cao, F. A. Durrani, and Y. M. Rustum Lack of Microvessels in Well-Differentiated Regions of Human Head and Neck Squamous Cell Carcinoma A253 Associated with Functional Magnetic Resonance Imaging Detectable Hypoxia, Limited Drug Delivery, and Resistance to Irinotecan Therapy Clin. Cancer Res., December 1, 2004; 10(23): 8005 - 8017. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Kaluzova, S. Kaluz, M. I. Lerman, and E. J. Stanbridge DNA Damage Is a Prerequisite for p53-Mediated Proteasomal Degradation of HIF-1{alpha} in Hypoxic Cells and Downregulation of the Hypoxia Marker Carbonic Anhydrase IX Mol. Cell. Biol., July 1, 2004; 24(13): 5757 - 5766. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. G. Kharas, J. A. Deane, S. Wong, K. R. O'Bosky, N. Rosenberg, O. N. Witte, and D. A. Fruman Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells Blood, June 1, 2004; 103(11): 4268 - 4275. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Hopfl, O. Ogunshola, and M. Gassmann HIFs and tumors--causes and consequences Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623. [Abstract] [Full Text] [PDF] |
||||
![]() |
G.-i. Kusakai, A. Suzuki, T. Ogura, S.'i. Miyamoto, A. Ochiai, M. Kaminishi, and H. Esumi ARK5 Expression in Colorectal Cancer and Its Implications for Tumor Progression Am. J. Pathol., March 1, 2004; 164(3): 987 - 995. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. M. Crawford, S. Jovanovic, G. R. Budas, A. M. Davies, H. Lad, R. H. Wenger, K. A. Robertson, D. J. Roy, H. J. Ranki, and A. Jovanovic Chronic Mild Hypoxia Protects Heart-derived H9c2 Cells against Acute Hypoxia/Reoxygenation by Regulating Expression of the SUR2A Subunit of the ATP-sensitive K+ Channel J. Biol. Chem., August 15, 2003; 278(33): 31444 - 31455. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Kaluz, M. Kaluzova, and E. J. Stanbridge Expression of the Hypoxia Marker Carbonic Anhydrase IX Is Critically Dependent on SP1 Activity. Identification of a Novel Type of Hypoxia-responsive Enhancer Cancer Res., March 1, 2003; 63(5): 917 - 922. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |