HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas

Gray, Michael J.; Zhang, Jing; Ellis, Lee M.; Semenza, Gregg L.; Evans, Douglas B.; Watowich, Stephanie S.; Gallick, Gary E.

doi:10.1038/sj.onc.1208513

Cited by 350 publications

(330 citation statements)

References 77 publications

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“…Furthermore, the stimulation of cancer cells with IL-1β (4 hours) led to an increased amount of HIF-1α/ KLF5 protein complex that immunoprecipitated. This novel finding suggests a potential functional interaction of HIF-1α with KLF5, a feature that has also been shown for other proteins and transcription factors in terms of binding to HIF-1α, such as STAT3, Ref-1/APE, and Hsp90 (27,36). The involvement of HIF-1α in the regulation of KLF5 was further supported by results from our experiments using transient RNAi for down-regulating either HIF-1α or KLF5 in cancer cells.…”

Section: Discussionsupporting

confidence: 82%

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk-mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1β or hypoxia. The IL-1 β-mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1α (HIF-1α) and HIF-1α siRNA reduced constitutive KLF5. Similarly, KLF5 siRNA reduced the expression of the HIF-1α target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/ MAPK/Erk signaling, but involves the IL-1β/IL-1R system, p38, and the transcription factor

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Section: Discussionsupporting

confidence: 82%

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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“…Additionally, STAT3 was found to be important for maximal VEGF expression in complex with HIF-1 and CBP/p300 in prostate and pancreatic carcinoma. 66 Conversely, the HIF proteins can also participate in transcriptional regulation of non-canonical pathways such as Myc and Notch signalling, where they are recruited to DNA via interaction with other transcription factors. 67 Finally, Hsp90 has been shown in a number of studies to be required for HIF activity, although this appears to be predominantly through regulation of HIF stability as described previously.…”

Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 99%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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“…Oncogenic signaling pathways in turn converge upon a limited set of nuclear transcription factors, the final 'switches' determining gene expression patterns and ultimately leading to malignancy (Darnell, 2002). Recent work by Gray et al (2005) also demonstrates that binding of both Stat3 and HIF to the VEGF promoter is required for optimal VEGF expression under hypoxia. Together with our findings, these results add a new dimension to the importance of targeting key transcription factors for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways

et al. 2005

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HIF-1α, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas

Cited by 350 publications

References 77 publications

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Turn me on: regulating HIF transcriptional activity

Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways

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