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Hypoxia-inducible Factor-1 Is a Positive Factor in Solid Tumor Growth

Department of Biology, University of California, San Diego, California 92093 [H. E. R., M. P., W. M., R. S. J.]; Cancer Genetics Program, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California 94143 [D. E., J. M. A.]; and Institute of Physiology, University of Zurich-Irchel, CH-8057 Zurich, Switzerland [M. G.]

	ABSTRACT

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Deficiencies in oxygenation are widespread in solid tumors. The transcription factor hypoxia-inducible factor (HIF)-1 is an important mediator of the hypoxic response of tumor cells and controls the up-regulation of a number of factors important for solid tumor expansion, including the angiogenic factor vascular endothelial growth factor (VEGF). We have isolated two cell lines nullizygous for HIF-1, one from embryos genetically null for HIF-1, and the other from embryos carrying loxP-flanked alleles of the gene, which allows for cre-mediated excision. The loss of HIF-1 negatively affects tumor growth in these two sets of H-ras-transformed cell lines, and this negative effect is not due to deficient vascularization. Despite differences in VEGF expression, vascular density is similar in wild-type and HIF-1-null tumors. The evidence from these experiments indicates that hypoxic response via HIF-1 is an important positive factor in solid tumor growth and that HIF-1 affects tumor expansion in ways unrelated to its regulation of VEGF expression.

	Introduction

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To understand the biology of tumor growth, it is critical to also understand the cellular response to changes in oxygen tension. The process of tumor expansion is characterized by rapid growth as a tumor establishes itself in the host. Accompanying this rapid growth are alterations in the microenvironment of the tumor cells, typically caused by an inability of the local vasculature to supply enough oxygen and nutrients to rapidly dividing tumor cells (1) . Whereas the hypoxia that results may inhibit new cell division or even lead to cell death (2, 3, 4, 5) , it can also lead to adaptive responses that will help the cells survive (6) . These responses include an induction of angiogenesis and a switch to anaerobic metabolism; in addition, hypoxia can act as a selective force within a tumor for cells that harbor mutations, further improving their chance for survival (7) . Hypoxia thus represents a paradox for those studying tumor growth: although oxygen deprivation can have negative effects on cell growth, the hypoxic response can mitigate those effects and even drive critical tumorigenic adaptations.

Control of the hypoxic response in mammalian cells occurs through a number of mechanisms, primarily transcriptional and posttranscriptional mechanisms (8) . The transcription factor HIF-1² is one of the major regulators of hypoxic response (reviewed in Ref. 9 ) and was first identified by Semenza and colleagues (10, 11, 12) as a regulator of hypoxia-induced erythropoietin expression. The HIF-1 binding site was then found on a wide range of promoter elements of genes up-regulated by hypoxia. This provided the first indication that there was a common mechanism regulating hypoxic response via transcription. The activation of transcription by HIF-1 occurs through the oxygen-regulated stabilization of HIF-1, followed by its dimerization with ARNT, a constitutively expressed protein. Two other hypoxia-responsive homologues of the HIF-1 gene have been cloned, yet there appears to be little redundancy in hypoxic response (13, 14, 15, 16, 17) . In cells examined thus far, the loss of HIF-1 results in a total loss of binding to HIF-1 response elements (18 , 19) .

The hypoxic response would appear to promote tumor growth by promoting cell survival; this likely occurs through its induction of angiogenesis and its activation of anaerobic metabolism. Initial data have indicated that this is likely the case because loss of either HIF-1 or ARNT has been shown to retard tumor growth (19 , 20) . The mechanism for this retardation appears to be decreased vascularization accompanied by an increase in apoptosis. The decrease in vascularization presumably occurs in part through a loss of HIF-1-mediated expression of a critical effector of tumor angiogenesis, VEGF. These tumor data support a model in which the primary role of tumor hypoxia and the hypoxic response is to promote tumor angiogenesis. The role of HIF-1 as a tumor-promoting factor has become a controversial point, however, because recent work by one group has indicated that HIF-1 acts as a tumor suppressor, or negative factor, in ES cell-derived tumors (21) .

We have further explored this important issue through the generation of differentiated, genetically manipulated cell lines nullizygous for HIF-1. We report here the generation of wild-type and HIF-1-null H-ras- transformed mEFs. Our findings confirm that HIF-1 acts as a positive regulator of tumor growth in this cell type as well. Surprisingly, we found no difference in vascular density between wild-type and null tumors, despite the fact that VEGF induction under hypoxia was significantly reduced both in vitro and in vivo. Our data demonstrate that HIF-1 is a positive regulator of tumor growth after H-ras transformation of fibroblasts and that the loss of HIF-1 alters VEGF expression in vivo during solid tumor formation without a concomitant effect on vascular density in null tumors. Furthermore, we demonstrate that the cre/loxP system will provide a useful way to understand the role of HIF-1 and the hypoxic response in other processes.

	Materials and Methods

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Creation of Mice Carrying a loxP-flanked Allele of HIF-1.
Genomic DNA was obtained as described previously (19) . A loxP site was engineered in the first intron through PCR, and a loxP-flanked neomycin resistance cassette was cloned into a SphI site in the second intron. The targeting vector was linearized, and 20 µg of the vector were electroporated into R1 ES cells (22) . The neomycin resistance cassette was removed by electroporation of 30 µg of a cre-expressing plasmid into targeted cells [pML 78 (23 , 24) ]. PCR was used to identify cell lines that had maintained loxP sites on either side of exon 2. Chimeric mice were generated by injection of ES cells into C57Bl/6 blastocysts (25) .

Isolation of Wild-Type and HIF-1-null mEFs.
Wild-type and HIF-1-null embryos were harvested at embryonic day 9.5, dissociated by incubation in 0.25% trypsin (Life Technologies, Inc.), and cultured. Embryos carrying two loxP-flanked alleles of HIF-1 were harvested at embryonic day 13.5, dissociated by passage through an 18-gauge needle, and cultured. Cells were immortalized by stable transfection of SV40 large T antigen, using Superfectamine (Qiagen) according to the manufacturer’s instructions and transformed by infection with a retrovirus expressing H-ras (26) . The +^f/+^fras/TAg cells were infected with adenovirus expressing either ß-galactosidase or cre recombinase.

The wild-type or null status of cells was confirmed by standard Southern blotting. Nuclear extracts were isolated from normoxic and hypoxic (4 h) cells by incubation in cell lysis buffer [10 mM Tris-HCl (pH 8.0), 1 mM EDTA (pH 8.0), 150 mM NaCl, 0.5% NP40, 1 µg/ml aprotinin, 1 µg/ml pepstatin A, 1 µg/ml leupeptin, and 1 mM phenylmethylsulfonyl fluoride] and separation of the nuclei by centrifugation. Nuclei were lysed by incubation in a buffer containing 20 mM HEPES (pH 7.9), 400 mM NaCl, 1 mM EDTA (pH 8.0), and 1 mM DTT. Extracts were analyzed by SDS-PAGE, electroblotting, and immunodetection with an anti-HIF-1 IgY antibody (27) . Detection of HIF-1 was performed using a horseradish peroxidase-conjugated goat anti-IgY (Promega) secondary antibody and SuperSignal West Femto reagent from Pierce.

Target Gene Analysis.
Cells were cultured for 0 or 8 h under hypoxia, and RNA was extracted with Trizol reagent (Life Technologies, Inc.) according to the manufacturer’s protocol. Approximately 15 µg of total RNA were loaded per lane, run on a 1% denaturing agarose gel, and hybridized with cDNA probes. Probes were generated as described in Ryan et al. (19) .

Generation of Fibrosarcomas.
A total of 1 x 10⁷ cells were injected s.c. intrascapularly into immunocompromised mice, either RAG1-/- mice (28) or nu/nu mice from Charles River. Tumors were harvested 16–18 days after injection, weighed, and processed for histology.

Tumor Histology.
Sections were cut from frozen tissue and stained for CD31 as described previously. Vessel density in the most vascular regions of the tumor was determined with a Chalkley eyepiece graticule as described by Fox et al. (29) .

In situ hybridization was performed on paraformaldehyde-fixed, paraffin-embedded sections using ³⁵S-UTP-labeled riboprobes as described previously (30 , 31) .

	Results

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Creation of HIF-1-null H-ras-transformed Cell Lines.
To carry out initial characterization of differentiated cells that lack a functional HIF-1 allele, we generated lines directly from HIF-1 wild-type and null embryos. Embryos were harvested at embryonic day 9.5 and cells were immediately immortalized by stable transfection with SV40 large T antigen (32) . The cells were transformed by infection with a retrovirus expressing the activated H-ras allele (26) . Analysis of these cell lines by DNA and protein blotting confirmed their wild-type or null status, and they are referred to hereafter as +/+ ras/TAg or -/- ras/TAg cell lines (Fig. 1 , C and D).

View larger version (40K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Generation of a loxP-flanked allele of HIF-1. A, diagram of the strategy used to replace the endogenous HIF-1 locus with a loxP-flanked locus. Genomic structure after targeting and cre expression. A, AflIII; B, BamHI; Bg, BglII; P, PstI; X, XbaI. B, Southern blot analysis of the HIF-1 locus before cre expression showing a BamHI digest of genomic DNA and hybridization to a 5' external probe. C, Southern blot analysis of genomic DNA from mEF ras/TAg cell lines demonstrating either loss of the second exon (-f/-f, PstI/EcoRI digest) or deletion of the second exon and intron (-/-, BamHI digest). D, Western blot analysis of mEF ras/TAg cell lines showing induction of HIF-1 after 4 h of hypoxia (1% O2) in wild-type cells and loss of hypoxia-induced HIF-1 expression in the null cells. E, Northern blot analysis of 15 µg of total RNA from wild-type and HIF-1-null cells after 0 or 8 h of hypoxia. Left, the cDNA probe used for hybridization.

We designed a conditional allele of HIF-1 in which the second exon is flanked by loxP sites. The second exon encodes the helix-loop-helix motif, which has been shown to be essential for HIF-1 dimerization with ARNT and subsequent transcriptional activation (34) . The targeting vector contains a loxP site in the first intron and a loxP-flanked neomycin resistance gene in the second intron (Fig. 1A ). Homologous recombination at the HIF-1 locus results in an allele with a loxP site 5' of exon 2 and the loxP-flanked neomycin resistance gene 3' of exon 2 (Fig. 1B ). It is possible that the presence of the neomycin resistance gene in the second intron could affect proper expression of HIF-1; to safeguard against this possibility, we transiently expressed cre recombinase in the targeted ES cells. A fraction of the ES cells excised the neomycin resistance gene but retained 5' and 3' loxP sites, whose presence was confirmed by PCR (data not shown). These ES cell clones were used for the generation of chimeras and mouse strains via blastocyst injection (25) .

Mice containing loxP-flanked alleles of HIF-1 were crossed, and mEFs were harvested from embryonic day 13.5 embryos that were homozygous (+^f/+^f) for the conditionally targeted allele. The cells were transformed with SV40 large T antigen and H-ras as described above.

We next generated HIF-1-null cells by transiently expressing cre recombinase to delete the loxP-flanked second exon. We used adenovirus to transiently express cre recombinase in +^f/+^f ras/TAg cell lines. An adenovirus expressing ß-galactosidase was also used to infect +^f/+^fras/TAg cells. These ß-galactosidase-infected cells were then used as wild-type controls in all of the following experiments and are referred to as +^f/+^fras/TAg cells. Cre-infected cells are referred to as -^f/-^f ras/Tag cells. Four to five days after infection, cells were assayed for excision of the second exon. DNA analysis via Southern blotting (Fig. 1C ) and PCR (data not shown) indicated complete excision of the second exon in the entire cell population. This was further confirmed by analysis of nuclear extracts from the conditionally targeted cells, which showed an absence of HIF-1 protein under hypoxic conditions (Fig. 1D ). ß-Galactosidase-infected cells maintained a wild-type Southern profile and expressed HIF-1 under hypoxia (Fig. 1 and D ). Both cell lines grew at similar rates in culture and formed similar numbers of colonies in soft agar assays (data not shown).

Loss of Hypoxia-mediated Transcriptional Induction in HIF-1-null mEFs.
HIF-1 regulates a wide array of genes in response to hypoxia. The loss of HIF-1 in ES cells leads to a reduction in hypoxic expression of VEGF and a number of other genes at the mRNA level (18 , 19) . We assayed both of the HIF-1-null mEF cell lines for loss of target gene expression by Northern blotting (Fig. 1E ). In the -^f/-^f ras/TAg cell line, the absence of HIF-1 lessens the hypoxic induction of VEGF and completely inhibits that of the hypoxia-responsive genes phosphoglycerate kinase, lactate dehydrogenase, and glucose transporter-1. The situation is similar in the -/- ras/TAg cell line.

HIF-1 Is a Positive Regulator of Tumor Growth.
The wild-type and null transformed cell lines described above were used to create fibrosarcomas in immunocompromised animals. Cells were injected s.c., and at 16–18 days after injection, the tumors were harvested and weighed. In both sets of cell lines, the absence of HIF-1 resulted in a significant decrease in tumor mass (Fig. 2 ).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Loss of HIF-1 leads to a reduction in tumor mass. A, analysis of tumor mass from +/+ ras/TAg (n = 10) and -/-ras/TAg (n = 10) tumors. B, analysis of tumor mass from +f/+f ras/TAg (n = 20) and -f/-f ras/TAg (n = 16) tumors. Statistical analysis was performed using Statview (Abacus Software).

View larger version (99K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Loss of HIF-1 does not affect vessel density within tumors. A, CD31 staining of frozen tumor sections showing no obvious difference in vessel density. Magnification, x100. B, analysis of Chalkley scores confirming no statistical difference in vessel density between wild-type and null tumors.

View larger version (136K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Absence of HIF-1 affects VEGF expression within a tumor. In situ hybridization demonstrating the punctate pattern of VEGF expression in -f/-f ras/TAg tumors. A, dark-field view at a magnification of x100 (right), alongside a bright-field image of the same region. Exposure times for the dark-field photos were identical. B, bright-field view at a higher magnification (x400). Black dots are exposed silver grains.

	Discussion

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Data published previously on the mechanism by which HIF-1 positively regulates tumor growth have focused on angiogenesis (19, 20, 21 , 39) . The consensus has been that the absence of either HIF-1 or its dimerization partner, ARNT, leads to reduced vascularization within a tumor due to a reduced capacity to hypoxically induce VEGF expression. We were therefore surprised to find that loss of HIF-1 did not alter tumor vascularization in H-ras-transformed fibrosarcomas. This is in contrast to experiments in which VEGF itself is deleted from tumor cells, causing a large decrease in vascular density (35) , and in contrast to the experimental evidence from ES cell-derived tumors, where significant, albeit subtle, differences in vascular density are seen (19 , 21) .

We considered the possibility that our observation might be due to differences between in vitro and in vivo VEGF expression, where the tumor environment works in such a way as to make expression differences seen in culture inconsequential in vivo. This may explain our observations; however, within the tumors, in situ hybridization demonstrates that there are clear differences in VEGF expression between +^f/+^f and -^f/-^f tumors. This difference is best seen in the higher magnification in Fig. 4B , which shows that VEGF expression within these tumors is more punctate and restricted. A possible explanation for the different expression pattern seen in the -^f/-^f tumors is that a higher degree of hypoxia is required to stimulate VEGF expression in these cells and that this more restricted expression pattern is an indication of those regions. This high level of VEGF expression from a smaller number of cells may be able to compensate for a general reduction in VEGF expression, ultimately resulting in an adequate degree of vascularization.

The work presented here has clearly demonstrated that HIF-1 acts to promote tumor growth. What has become less clear is the exact mechanism by which HIF-1 functions in this capacity. Our fibrosarcoma model has provided the first indication that hypoxic induction of angiogenesis may play a smaller role in tumor growth than previously thought and that HIF-1-mediated regulation of VEGF is not crucial for tumor vascularization. With the multitude of HIF-1 target genes, there are a number of possible mechanisms yet to be investigated, and in all likelihood, the effect of HIF-1 on tumor growth is complex and involves the activation of several adaptive pathways. We also report for the first time the development of conditionally targeted mice and transformed cell lines from which HIF-1 can be easily excised via cre recombinase expression. These should prove invaluable reagents to investigators wishing to study the role of HIF-1 during normal development and the role of hypoxic response during tumorigenesis.

	Acknowledgments

 
We thank members of the Johnson laboratory for their support and advice throughout the course of this work and Keith Laderoute, Amato Giaccia, Robert Warren, Michael Karin, Gregg Semenza, Ronald Wisdom, and Frank Giordano for reagents and helpful advice.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at University of California, San Diego, Department of Biology, 9500 Gilman Drive, 0366, La Jolla, CA 92093-0366. Phone: (858) 822-0509; Fax: (858) 534-5831.

² The abbreviations used are: HIF, hypoxia-inducible factor; VEGF, vascular endothelial growth factor; mEF, mouse embryonic fibroblast; ARNT, aryl hydrocarbon receptor nuclear translocator; ES, embryonic stem; TAg, T antigen.

Received 4/ 9/00. Accepted 6/14/00.

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				J. Lu, K. Zhang, S. Chen, and W. Wen Grape seed extract inhibits VEGF expression via reducing HIF-1{alpha} protein expression Carcinogenesis, April 1, 2009; 30(4): 636 - 644. [Abstract] [Full Text] [PDF]

				J. A. Bertout, S. A. Patel, B. H. Fryer, A. C. Durham, K. L. Covello, K. P. Olive, M. H. Goldschmidt, and M. C. Simon Heterozygosity for Hypoxia Inducible Factor 1{alpha} Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model Cancer Res., April 1, 2009; 69(7): 3213 - 3220. [Abstract] [Full Text] [PDF]

				J. J. Lysiak, J. L. Kirby, J. J. Tremblay, R. I. Woodson, M. A. Reardon, L. A. Palmer, and T. T. Turner Hypoxia-Inducible Factor-1{alpha} Is Constitutively Expressed in Murine Leydig Cells and Regulates 3{beta}-Hydroxysteroid Dehydrogenase Type 1 Promoter Activity J Androl, March 1, 2009; 30(2): 146 - 156. [Abstract] [Full Text] [PDF]

				Y. Liu, C. K. Veena, J. B. Morgan, K. A. Mohammed, M. B. Jekabsons, D. G. Nagle, and Y.-D. Zhou Methylalpinumisoflavone Inhibits Hypoxia-inducible Factor-1 (HIF-1) Activation by Simultaneously Targeting Multiple Pathways J. Biol. Chem., February 27, 2009; 284(9): 5859 - 5868. [Abstract] [Full Text] [PDF]

				E. F. Moreira, I. M. Larrayoz, J. W. Lee, and I. R. Rodriguez 7-Ketocholesterol Is Present in Lipid Deposits in the Primate Retina: Potential Implication in the Induction of VEGF and CNV Formation Invest. Ophthalmol. Vis. Sci., February 1, 2009; 50(2): 523 - 532. [Abstract] [Full Text] [PDF]

				R. Wirthner, S. Wrann, K. Balamurugan, R. H. Wenger, and D. P. Stiehl Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1{alpha}-deficient mouse embryonic fibroblasts Carcinogenesis, December 1, 2008; 29(12): 2306 - 2316. [Abstract] [Full Text] [PDF]

				Y. Saini, J. R. Harkema, and J. J. LaPres HIF1{alpha} Is Essential for Normal Intrauterine Differentiation of Alveolar Epithelium and Surfactant Production in the Newborn Lung of Mice J. Biol. Chem., November 28, 2008; 283(48): 33650 - 33657. [Abstract] [Full Text] [PDF]

				J. Krishnan, P. Ahuja, S. Bodenmann, D. Knapik, E. Perriard, W. Krek, and J.-C. Perriard Essential Role of Developmentally Activated Hypoxia-Inducible Factor 1{alpha} for Cardiac Morphogenesis and Function Circ. Res., November 7, 2008; 103(10): 1139 - 1146. [Abstract] [Full Text] [PDF]

				E. Sato, T. Torigoe, Y. Hirohashi, H. Kitamura, T. Tanaka, I. Honma, H. Asanuma, K. Harada, H. Takasu, N. Masumori, et al. Identification of an Immunogenic CTL Epitope of HIFPH3 for Immunotherapy of Renal Cell Carcinoma Clin. Cancer Res., November 1, 2008; 14(21): 6916 - 6923. [Abstract] [Full Text] [PDF]

				E. Favaro, G. Nardo, L. Persano, M. Masiero, L. Moserle, R. Zamarchi, E. Rossi, G. Esposito, M. Plebani, U. Sattler, et al. Hypoxia Inducible Factor-1{alpha} Inactivation Unveils a Link between Tumor Cell Metabolism and Hypoxia-Induced Cell Death Am. J. Pathol., October 1, 2008; 173(4): 1186 - 1201. [Abstract] [Full Text] [PDF]

				J.-H. Lim, Y.-S. Chun, and J.-W. Park Hypoxia-Inducible Factor-1{alpha} Obstructs a Wnt Signaling Pathway by Inhibiting the hARD1-Mediated Activation of {beta}-Catenin Cancer Res., July 1, 2008; 68(13): 5177 - 5184. [Abstract] [Full Text] [PDF]

				M. Puppo, F. Battaglia, C. Ottaviano, S. Delfino, D. Ribatti, L. Varesio, and M. C. Bosco Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1{alpha} and -2{alpha} Mol. Cancer Ther., July 1, 2008; 7(7): 1974 - 1984. [Abstract] [Full Text] [PDF]

				Y. Wang, M. Saad, R. I. Pakunlu, J. J. Khandare, O. B. Garbuzenko, A. A. Vetcher, V. A. Soldatenkov, V. P. Pozharov, and T. Minko Nonviral Nanoscale-Based Delivery of Antisense Oligonucleotides Targeted to Hypoxia-Inducible Factor 1{alpha} Enhances the Efficacy of Chemotherapy in Drug-Resistant Tumor Clin. Cancer Res., June 1, 2008; 14(11): 3607 - 3616. [Abstract] [Full Text] [PDF]

				K. Lee, J. D. Lynd, S. O'Reilly, M. Kiupel, J. J. McCormick, and J. J. LaPres The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential Mol. Cancer Res., May 1, 2008; 6(5): 829 - 842. [Abstract] [Full Text] [PDF]

				P. Vaupel Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis Oncologist, May 1, 2008; 13(suppl_3): 21 - 26. [Abstract] [Full Text] [PDF]

				B. J. Murphy, T. Kimura, B. G. Sato, Y. Shi, and G. K. Andrews Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1{alpha} Mol. Cancer Res., March 1, 2008; 6(3): 483 - 490. [Abstract] [Full Text] [PDF]

				X. Xu, R. Sutak, and D. R. Richardson Iron Chelation by Clinically Relevant Anthracyclines: Alteration in Expression of Iron-Regulated Genes and Atypical Changes in Intracellular Iron Distribution and Trafficking Mol. Pharmacol., March 1, 2008; 73(3): 833 - 844. [Abstract] [Full Text] [PDF]

				G. Vangeison, D. Carr, H. J. Federoff, and D. A. Rempe The Good, the Bad, and the Cell Type-Specific Roles of Hypoxia Inducible Factor-1{alpha} in Neurons and Astrocytes J. Neurosci., February 20, 2008; 28(8): 1988 - 1993. [Abstract] [Full Text] [PDF]

				M. Elser, L. Borsig, P. O. Hassa, S. Erener, S. Messner, T. Valovka, S. Keller, M. Gassmann, and M. O. Hottiger Poly(ADP-Ribose) Polymerase 1 Promotes Tumor Cell Survival by Coactivating Hypoxia-Inducible Factor-1-Dependent Gene Expression Mol. Cancer Res., February 1, 2008; 6(2): 282 - 290. [Abstract] [Full Text] [PDF]

				R. D. Guzy, B. Sharma, E. Bell, N. S. Chandel, and P. T. Schumacker Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis Mol. Cell. Biol., January 15, 2008; 28(2): 718 - 731. [Abstract] [Full Text] [PDF]

				F. Vumbaca, K. N. Phoenix, D. Rodriguez-Pinto, D. K. Han, and K. P. Claffey Double-Stranded RNA-Binding Protein Regulates Vascular Endothelial Growth Factor mRNA Stability, Translation, and Breast Cancer Angiogenesis Mol. Cell. Biol., January 15, 2008; 28(2): 772 - 783. [Abstract] [Full Text] [PDF]

				X. Lin, C. A. David, J. B. Donnelly, M. Michaelides, N. S. Chandel, X. Huang, U. Warrior, F. Weinberg, K. V. Tormos, S. W. Fesik, et al. A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation PNAS, January 8, 2008; 105(1): 174 - 179. [Abstract] [Full Text] [PDF]

				P. Pichiule, J. C. Chavez, A. M. Schmidt, and S. J. Vannucci Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia J. Biol. Chem., December 14, 2007; 282(50): 36330 - 36340. [Abstract] [Full Text] [PDF]

				A. J. Glassford, P. Yue, A. Y. Sheikh, H. J. Chun, S. Zarafshar, D. A. Chan, G. M. Reaven, T. Quertermous, and P. S. Tsao HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1590 - E1596. [Abstract] [Full Text] [PDF]

				R. Amarilio, S. V. Viukov, A. Sharir, I. Eshkar-Oren, R. S. Johnson, and E. Zelzer HIF1{alpha} regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis Development, November 1, 2007; 134(21): 3917 - 3928. [Abstract] [Full Text] [PDF]

				R. W. Bavis, F. L. Powell, A. Bradford, C. C.W. Hsia, J. E. Peltonen, J. Soliz, B. Zeis, E. K. Fergusson, Z. Fu, M. Gassmann, et al. Respiratory plasticity in response to changes in oxygen supply and demand Integr. Comp. Biol., October 1, 2007; 47(4): 532 - 551. [Abstract] [Full Text] [PDF]

				Y. Mizukami, Y. Kohgo, and D. C. Chung Hypoxia Inducible Factor-1 Independent Pathways in Tumor Angiogenesis Clin. Cancer Res., October 1, 2007; 13(19): 5670 - 5674. [Abstract] [Full Text] [PDF]

				Z. H. Lu, J. D. Wright, B. Belt, R. D. Cardiff, and J. M. Arbeit Hypoxia-Inducible Factor-1 Facilitates Cervical Cancer Progression in Human Papillomavirus Type 16 Transgenic Mice Am. J. Pathol., August 1, 2007; 171(2): 667 - 681. [Abstract] [Full Text] [PDF]

				O. Baranova, L. F. Miranda, P. Pichiule, I. Dragatsis, R. S. Johnson, and J. C. Chavez Neuron-Specific Inactivation of the Hypoxia Inducible Factor 1{alpha} Increases Brain Injury in a Mouse Model of Transient Focal Cerebral Ischemia J. Neurosci., June 6, 2007; 27(23): 6320 - 6332. [Abstract] [Full Text] [PDF]

				H. R. Rezvani, S. Dedieu, S. North, F. Belloc, R. Rossignol, T. Letellier, H. de Verneuil, A. Taieb, and F. Mazurier Hypoxia-inducible Factor-1{alpha}, a Key Factor in the Keratinocyte Response to UVB Exposure J. Biol. Chem., June 1, 2007; 282(22): 16413 - 16422. [Abstract] [Full Text] [PDF]

				D. A. Rempe, K. M. Lelli, G. Vangeison, R. S. Johnson, and H. J. Federoff In Cultured Astrocytes, p53 and MDM2 Do Not Alter Hypoxia-inducible Factor-1{alpha} Function Regardless of the Presence of DNA Damage J. Biol. Chem., June 1, 2007; 282(22): 16187 - 16201. [Abstract] [Full Text] [PDF]

				L. K. Martens, K. M. Kirschner, C. Warnecke, and H. Scholz Hypoxia-inducible Factor-1 (HIF-1) Is a Transcriptional Activator of the TrkB Neurotrophin Receptor Gene J. Biol. Chem., May 11, 2007; 282(19): 14379 - 14388. [Abstract] [Full Text] [PDF]

				J. J. Lum, T. Bui, M. Gruber, J. D. Gordan, R. J. DeBerardinis, K. L. Covello, M. C. Simon, and C. B. Thompson The transcription factor HIF-1{alpha} plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis Genes & Dev., May 1, 2007; 21(9): 1037 - 1049. [Abstract] [Full Text] [PDF]

				D. L. Gillespie, K. Whang, B. T. Ragel, J. R. Flynn, D. A. Kelly, and R. L. Jensen Silencing of Hypoxia Inducible Factor-1{alpha} by RNA Interference Attenuates Human Glioma Cell Growth In vivo Clin. Cancer Res., April 15, 2007; 13(8): 2441 - 2448. [Abstract] [Full Text] [PDF]

				K. Horii, Y. Suzuki, Y. Kondo, M. Akimoto, T. Nishimura, Y. Yamabe, M. Sakaue, T. Sano, T. Kitagawa, S. Himeno, et al. Androgen-Dependent Gene Expression of Prostate-Specific Antigen Is Enhanced Synergistically by Hypoxia in Human Prostate Cancer Cells Mol. Cancer Res., April 1, 2007; 5(4): 383 - 391. [Abstract] [Full Text] [PDF]

				A. Jalota-Badhwar, R. Kaul-Ghanekar, D. Mogare, R. Boppana, K. M. Paknikar, and S. Chattopadhyay SMAR1-derived P44 Peptide Retains Its Tumor Suppressor Function through Modulation of p53 J. Biol. Chem., March 30, 2007; 282(13): 9902 - 9913. [Abstract] [Full Text] [PDF]

				J. Tabernero The Role of VEGF and EGFR Inhibition: Implications for Combining Anti-VEGF and Anti-EGFR Agents Mol. Cancer Res., March 1, 2007; 5(3): 203 - 220. [Abstract] [Full Text] [PDF]

				J.-H. Lim, J.-W. Park, S. J. Kim, M.-S. Kim, S.-K. Park, R. S. Johnson, and Y.-S. Chun ATP6V0C Competes with Von Hippel-Lindau Protein in Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) Binding and Mediates HIF-1{alpha} Expression by Bafilomycin A1 Mol. Pharmacol., March 1, 2007; 71(3): 942 - 948. [Abstract] [Full Text] [PDF]

				M. Gruber, C.-J. Hu, R. S. Johnson, E. J. Brown, B. Keith, and M. C. Simon Acute postnatal ablation of Hif-2{alpha} results in anemia PNAS, February 13, 2007; 104(7): 2301 - 2306. [Abstract] [Full Text] [PDF]

				T. W. Young, F. C. Mei, D. G. Rosen, G. Yang, N. Li, J. Liu, and X. Cheng Up-regulation of Tumor Susceptibility Gene 101 Protein in Ovarian Carcinomas Revealed by Proteomics Analyses Mol. Cell. Proteomics, February 1, 2007; 6(2): 294 - 304. [Abstract] [Full Text] [PDF]

				J. Milosevic, M. Maisel, F. Wegner, J. Leuchtenberger, R. H. Wenger, M. Gerlach, A. Storch, and J. Schwarz Lack of Hypoxia-Inducible Factor-1{alpha} Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling J. Neurosci., January 10, 2007; 27(2): 412 - 421. [Abstract] [Full Text] [PDF]

				S. M. Welford, B. Bedogni, K. Gradin, L. Poellinger, M. Broome Powell, and A. J. Giaccia HIF1{alpha} delays premature senescence through the activation of MIF Genes & Dev., December 15, 2006; 20(24): 3366 - 3371. [Abstract] [Full Text] [PDF]

				J.-H. Lim, J.-W. Park, M.-S. Kim, S.-K. Park, R. S. Johnson, and Y.-S. Chun Bafilomycin Induces the p21-Mediated Growth Inhibition of Cancer Cells under Hypoxic Conditions by Expressing Hypoxia-Inducible Factor-1{alpha} Mol. Pharmacol., December 1, 2006; 70(6): 1856 - 1865. [Abstract] [Full Text] [PDF]

				S. Patiar and A. L Harris Role of hypoxia-inducible factor-1{alpha} as a cancer therapy target Endocr. Relat. Cancer, December 1, 2006; 13(Supplement_1): S61 - S75. [Abstract] [Full Text] [PDF]

				H. Choi, Y.-S. Chun, S.-W. Kim, M.-S. Kim, and J.-W. Park Curcumin Inhibits Hypoxia-Inducible Factor-1 by Degrading Aryl Hydrocarbon Receptor Nuclear Translocator: A Mechanism of Tumor Growth Inhibition Mol. Pharmacol., November 1, 2006; 70(5): 1664 - 1671. [Abstract] [Full Text] [PDF]

				Q. Ke and M. Costa Hypoxia-Inducible Factor-1 (HIF-1) Mol. Pharmacol., November 1, 2006; 70(5): 1469 - 1480. [Abstract] [Full Text] [PDF]

				D. Lukashev, B. Klebanov, H. Kojima, A. Grinberg, A. Ohta, L. Berenfeld, R. H. Wenger, A. Ohta, and M. Sitkovsky Cutting Edge: Hypoxia-Inducible Factor 1{alpha} and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes J. Immunol., October 15, 2006; 177(8): 4962 - 4965. [Abstract] [Full Text] [PDF]

				H. Chen, Y. Yan, T. L. Davidson, Y. Shinkai, and M. Costa Hypoxic Stress Induces Dimethylated Histone H3 Lysine 9 through Histone Methyltransferase G9a in Mammalian Cells. Cancer Res., September 15, 2006; 66(18): 9009 - 9016. [Abstract] [Full Text] [PDF]

				J. C. Chavez, O. Baranova, J. Lin, and P. Pichiule The Transcriptional Activator Hypoxia Inducible Factor 2 (HIF-2/EPAS-1) Regulates the Oxygen-Dependent Expression of Erythropoietin in Cortical Astrocytes J. Neurosci., September 13, 2006; 26(37): 9471 - 9481. [Abstract] [Full Text] [PDF]

				G. Melillo Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy Mol. Cancer Res., September 1, 2006; 4(9): 601 - 605. [Abstract] [Full Text] [PDF]

				L. Li, X. Lin, A. R. Shoemaker, D. H. Albert, S. W. Fesik, and Y. Shen Hypoxia-Inducible Factor-1 Inhibition in Combination with Temozolomide Treatment Exhibits Robust Antitumor Efficacy In vivo Clin. Cancer Res., August 1, 2006; 12(15): 4747 - 4754. [Abstract] [Full Text] [PDF]

				V. H. Haase Hypoxia-inducible factors in the kidney Am J Physiol Renal Physiol, August 1, 2006; 291(2): F271 - F281. [Abstract] [Full Text] [PDF]

				K. R. Laderoute, K. Amin, J. M. Calaoagan, M. Knapp, T. Le, J. Orduna, M. Foretz, and B. Viollet 5'-AMP-Activated Protein Kinase (AMPK) Is Induced by Low-Oxygen and Glucose Deprivation Conditions Found in Solid-Tumor Microenvironments. Mol. Cell. Biol., July 1, 2006; 26(14): 5336 - 5347. [Abstract] [Full Text] [PDF]

				Y. Mizukami, K. Fujiki, E.-M. Duerr, M. Gala, W.-S. Jo, X. Zhang, and D. C. Chung Hypoxic Regulation of Vascular Endothelial Growth Factor through the Induction of Phosphatidylinositol 3-Kinase/Rho/ROCK and c-Myc J. Biol. Chem., May 19, 2006; 281(20): 13957 - 13963. [Abstract] [Full Text] [PDF]

				E. B. Rankin, J. E. Tomaszewski, and V. H. Haase Renal cyst development in mice with conditional inactivation of the von hippel-lindau tumor suppressor. Cancer Res., March 1, 2006; 66(5): 2576 - 2583. [Abstract] [Full Text] [PDF]

				G. Kurban, V. Hudon, E. Duplan, M. Ohh, and A. Pause Characterization of a von Hippel Lindau Pathway Involved in Extracellular Matrix Remodeling, Cell Invasion, and Angiogenesis Cancer Res., February 1, 2006; 66(3): 1313 - 1319. [Abstract] [Full Text] [PDF]

				D. T. Dang, F. Chen, L. B. Gardner, J. M. Cummins, C. Rago, F. Bunz, S. V. Kantsevoy, and L. H. Dang Hypoxia-Inducible Factor-1{alpha} Promotes Nonhypoxia-Mediated Proliferation in Colon Cancer Cells and Xenografts Cancer Res., February 1, 2006; 66(3): 1684 - 1693. [Abstract] [Full Text] [PDF]

				S. Amir, R. Wang, H. Matzkin, J. W. Simons, and N. J. Mabjeesh MSF-A Interacts with Hypoxia-Inducible Factor-1{alpha} and Augments Hypoxia-Inducible Factor Transcriptional Activation to Affect Tumorigenicity and Angiogenesis Cancer Res., January 15, 2006; 66(2): 856 - 866. [Abstract] [Full Text] [PDF]

				M. P. Biju, Y. Akai, N. Shrimanker, and V. H. Haase Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1217 - F1226. [Abstract] [Full Text] [PDF]

				A. K. Neumann, J. Yang, M. P. Biju, S. K. Joseph, R. S. Johnson, V. H. Haase, B. D. Freedman, and L. A. Turka Hypoxia inducible factor 1{alpha} regulates T cell receptor signal transduction PNAS, November 22, 2005; 102(47): 17071 - 17076. [Abstract] [Full Text] [PDF]

				R. Bilton, N. Mazure, E. Trottier, M. Hattab, M.-A. Dery, D. E. Richard, J. Pouyssegur, and M. C. Brahimi-Horn Arrest-defective-1 Protein, an Acetyltransferase, Does Not Alter Stability of Hypoxia-inducible Factor (HIF)-1{alpha} and Is Not Induced by Hypoxia or HIF J. Biol. Chem., September 2, 2005; 280(35): 31132 - 31140. [Abstract] [Full Text] [PDF]

				L. Li, X. Lin, M. Staver, A. Shoemaker, D. Semizarov, S. W. Fesik, and Y. Shen Evaluating Hypoxia-Inducible Factor-1{alpha} as a Cancer Therapeutic Target via Inducible RNA Interference In vivo Cancer Res., August 15, 2005; 65(16): 7249 - 7258. [Abstract] [Full Text] [PDF]

				D. A. Chan, P. D. Sutphin, S.-E. Yen, and A. J. Giaccia Coordinate Regulation of the Oxygen-Dependent Degradation Domains of Hypoxia-Inducible Factor 1{alpha} Mol. Cell. Biol., August 1, 2005; 25(15): 6415 - 6426. [Abstract] [Full Text] [PDF]

				T Gaber, R Dziurla, R Tripmacher, G R Burmester, and F Buttgereit Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do! Ann Rheum Dis, July 1, 2005; 64(7): 971 - 980. [Abstract] [Full Text] [PDF]

				N.-M. Chau, P. Rogers, W. Aherne, V. Carroll, I. Collins, E. McDonald, P. Workman, and M. Ashcroft Identification of Novel Small Molecule Inhibitors of Hypoxia-Inducible Factor-1 That Differentially Block Hypoxia-Inducible Factor-1 Activity and Hypoxia-Inducible Factor-1{alpha} Induction in Response to Hypoxic Stress and Growth Factors Cancer Res., June 1, 2005; 65(11): 4918 - 4928. [Abstract] [Full Text] [PDF]

				R. D. Leek, I. Stratford, and A. L. Harris The Role of Hypoxia-Inducible Factor-1 in Three-dimensional Tumor Growth, Apoptosis, and Regulation by the Insulin-Signaling Pathway Cancer Res., May 15, 2005; 65(10): 4147 - 4152. [Abstract] [Full Text] [PDF]

				R. Helton, J. Cui, J. R. Scheel, J. A. Ellison, C. Ames, C. Gibson, B. Blouw, L. Ouyang, I. Dragatsis, S. Zeitlin, et al. Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1{alpha} Reduces Rather Than Increases Hypoxic-Ischemic Damage J. Neurosci., April 20, 2005; 25(16): 4099 - 4107. [Abstract] [Full Text] [PDF]

				E. B. Rankin, D. F. Higgins, J. A. Walisser, R. S. Johnson, C. A. Bradfield, and V. H. Haase Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice Mol. Cell. Biol., April 15, 2005; 25(8): 3163 - 3172. [Abstract] [Full Text] [PDF]

				K. L. Covello, M. C. Simon, and B. Keith Targeted Replacement of Hypoxia-Inducible Factor-1{alpha} by a Hypoxia-Inducible Factor-2{alpha} Knock-in Allele Promotes Tumor Growth Cancer Res., March 15, 2005; 65(6): 2277 - 2286. [Abstract] [Full Text] [PDF]

				L. Xie, R. S. Johnson, and R. S. Freeman Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1 J. Cell Biol., March 14, 2005; 168(6): 911 - 920. [Abstract] [Full Text] [PDF]

				J.-P. Piret, E. Minet, J.-P. Cosse, N. Ninane, C. Debacq, M. Raes, and C. Michiels Hypoxia-inducible Factor-1-dependent Overexpression of Myeloid Cell Factor-1 Protects Hypoxic Cells against tert-Butyl Hydroperoxide-induced Apoptosis J. Biol. Chem., March 11, 2005; 280(10): 9336 - 9344. [Abstract] [Full Text] [PDF]

				C. Tan, R. G. de Noronha, A. J. Roecker, B. Pyrzynska, F. Khwaja, Z. Zhang, H. Zhang, Q. Teng, A. C. Nicholson, P. Giannakakou, et al. Identification of a Novel Small-Molecule Inhibitor of the Hypoxia-Inducible Factor 1 Pathway Cancer Res., January 15, 2005; 65(2): 605 - 612. [Abstract] [Full Text] [PDF]

				A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF]

				D. F. Higgins, M. P. Biju, Y. Akai, A. Wutz, R. S. Johnson, and V. H. Haase Hypoxic induction of Ctgf is directly mediated by Hif-1 Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1223 - F1232. [Abstract] [Full Text] [PDF]

				X. Zhang, T. Kon, H. Wang, F. Li, Q. Huang, Z. N. Rabbani, J. P. Kirkpatrick, Z. Vujaskovic, M. W. Dewhirst, and C.-Y. Li Enhancement of Hypoxia-Induced Tumor Cell Death In vitro and Radiation Therapy In vivo by Use of Small Interfering RNA Targeted to Hypoxia-Inducible Factor-1{alpha} Cancer Res., November 15, 2004; 64(22): 8139 - 8142. [Abstract] [Full Text] [PDF]

				P. Vaupel The Role of Hypoxia-Induced Factors in Tumor Progression Oncologist, November 1, 2004; 9(suppl_5): 10 - 17. [Abstract] [Full Text] [PDF]

				N. T.V. Le and D. R. Richardson Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation Blood, November 1, 2004; 104(9): 2967 - 2975. [Abstract] [Full Text] [PDF]

				H. D. Skinner, J. Z. Zheng, J. Fang, F. Agani, and B.-H. Jiang Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated by Hypoxia-inducible Factor 1{alpha}, HDM2, and p70S6K1 in Response to Phosphatidylinositol 3-Kinase/AKT Signaling J. Biol. Chem., October 29, 2004; 279(44): 45643 - 45651. [Abstract] [Full Text] [PDF]

				M. P. Biju, A. K. Neumann, S. J. Bensinger, R. S. Johnson, L. A. Turka, and V. H. Haase Vhlh Gene Deletion Induces Hif-1-Mediated Cell Death in Thymocytes Mol. Cell. Biol., October 15, 2004; 24(20): 9038 - 9047. [Abstract] [Full Text] [PDF]

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