Inhibition of GSK3β by indirubins restores HIF‐1α accumulation under prolonged periods of hypoxia/anoxia

Schnitzer, Steffen E.; Schmid, Tobias; Zhou, Jie; Eisenbrand, Gerhard; Brüne, Bernhard

doi:10.1016/j.febslet.2004.12.023

Cited by 35 publications

(35 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, activation of ERK1/2 did not affect HIF-1␣ mRNA levels. In line, several studies have identified the PI3K/AKT pathway as an important element in hypoxic induction of HIF-1␣ protein and activity (Kietzmann et al, 2003;Mottet et al, 2003a;Schnitzer et al, 2005;Lee et al, 2006). In addition, the PI3K pathway is also involved in the activation of NFB (Sizemore et al, 1999;Madrid et al, 2000), and in fact, inhibitors of PI3K but not of ERK1/2 prevented activation of NFB by hypoxia, indicating that PI3K/AKT activates HIF-1␣ indirectly by inducing NFB.…”

Section: Nfb Is Activated By Hypoxia and Mediates The Induction Of Himentioning

confidence: 72%

Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells

BelAiba

Bonello

Zähringer

et al. 2007

MBoC

391

309

View full text Add to dashboard Cite

The oxygen sensitive ␣-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1␣ by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1␣ mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1␣ mRNA levels and HIF-1␣ promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1␣ mRNA and HIF-1␣ promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-B (NFB) nuclear translocation and activity. In line, expression of the NFB subunits p50 and p65 enhanced HIF-1␣ mRNA levels, whereas blocking of NFB by an inhibitor of nuclear factor-B attenuated HIF-1␣ mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFB site within the HIF-1␣ promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFB subunits to the HIF-1␣ promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1␣ mRNA expression via the PI3K/AKT pathway and activation of NFB.

show abstract

Section: Nfb Is Activated By Hypoxia and Mediates The Induction Of Himentioning

confidence: 72%

Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells

BelAiba

Bonello

Zähringer

et al. 2007

MBoC

391

309

View full text Add to dashboard Cite

show abstract

“…52 Interestingly, hypoxic conditions were shown to inhibit the activity of the PI3K pathway, in an experimental system similar to that where the effect of hypoxia on p53 was described. 53,54 Thus, the molecular mechanisms underlying stabilization of the p53 protein overlap only partially with those controlling its activation as a transcriptional activator. In this regard, the precise roles of specific post-translational modifications or coactivators may be cell-type and cell-context dependent.…”

Section: Discussionmentioning

confidence: 99%

The PI3K inhibitor LY294002 prevents p53 induction by DNA damage and attenuates chemotherapy-induced apoptosis

et al. 2005

View full text Add to dashboard Cite

The p53 tumor suppressor plays a key role in the natural protection against cancer. Activation of p53 by DNAdamaging agents can contribute to successful elimination of cancer cells via chemotherapy-induced apoptosis. The phosphatidylinositol-3 kinase (PI3K) pathway, triggered in normal cells upon exposure to growth factors, regulates a cascade of proliferation and survival signals. The PI3K pathway is abnormally active in many cancers, thus making it an attractive target for inactivation in an attempt to achieve better cancer therapy. We report here that exposure to LY294002, a potent PI3K inhibitor, aborts the activation of p53 by several drugs commonly used in cancer chemotherapy. Concomitantly, LY294002 attenuates p53-dependent, chemotherapy-induced apoptosis of cancer cells. These findings invoke an unexpected positive role for PI3K in p53 activation by anticancer agents, and suggest that the efficacy of PI3K inhibitors in cancer therapy may be greatly affected by the tumor p53 status.

show abstract

“…The AKT/GSK3 signaling pathway regulates HIF-1␣ protein stability (11,50). Inhibition of GSK3␤ activation by LiCl or overexpression of dominant negative GSK3␤ mutant is known to increase of HIF-1␣ expression and activity (52,53). Furthermore, various reports show that the transcription factor Snail is regulated by growth factors or integrins (6 -8).…”

Section: Discussionmentioning

confidence: 99%

Aldose Reductase Inhibition Prevents Hypoxia-induced Increase in Hypoxia-inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) by Regulating 26 S Proteasome-mediated Protein Degradation in Human Colon Cancer Cells

Tammali¹,

Saxena²,

Srivastava³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The development of intratumoral hypoxia, a hallmark of rapidly progressing solid tumors, renders tumor cells resistant to chemotherapy and radiation therapy. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes the reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mouse xenografts by inhibiting the NF-B-dependent activation of oxidative stress-mediated inflammatory and carcinogenic markers. However, the role of AR in mediating hypoxic stress signals is not known. We therefore investigated the molecular mechanisms by which AR inhibition prevents the hypoxia-induced human colon cancer cells growth and invasion. Our results indicate that AR inhibition by the pharmacological inhibitor fidarestat or ablation by AR-specific siRNA prevents hypoxia-induced proliferation of HT29, SW480, and Caco-2 colon cancer cells. Furthermore, hypoxia-induced increase in the level of HIF-1␣ in colon cancer cells was significantly decreased by AR inhibition. During hypoxic conditions, treatment of HT29 cells with the AR inhibitor fidarestat significantly decreased the expression of vascular endothelial growth factor, a down target of HIF-1␣, at both mRNA and protein levels and also prevented the activation of PI3K/AKT, GSK3␤, Snail, and lysyl oxidase. Furthermore, inhibition of hypoxia-induced HIF-1␣ protein accumulation by AR inhibition was abolished in the presence of MG132, a potent inhibitor of the 26 S proteasome. In addition, AR inhibition also prevented the hypoxiainduced inflammatory molecules such as Cox-2 and PGE2 and expression of extracellular matrix proteins such as MMP2, vimentin, uPAR, and lysyl oxidase 2. In conclusion, our results indicate that AR mediates hypoxic signals, leading to tumor progression and invasion.

show abstract

Inhibition of GSK3β by indirubins restores HIF‐1α accumulation under prolonged periods of hypoxia/anoxia

Cited by 35 publications

References 26 publications

Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells

Hypoxia Up-Regulates Hypoxia-Inducible Factor-1α Transcription by Involving Phosphatidylinositol 3-Kinase and Nuclear Factor κB in Pulmonary Artery Smooth Muscle Cells

The PI3K inhibitor LY294002 prevents p53 induction by DNA damage and attenuates chemotherapy-induced apoptosis

Aldose Reductase Inhibition Prevents Hypoxia-induced Increase in Hypoxia-inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) by Regulating 26 S Proteasome-mediated Protein Degradation in Human Colon Cancer Cells

Contact Info

Product

Resources

About