The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53–p21 axis

Pelletier, Joffrey; Dayan, Frédéric; Durivault, Jérôme; Ilc, Karine; Pécou, Elisabeth; Pouysségur, Jacques; Mazure, Nathalie M.

doi:10.1038/onc.2011.471

Cited by 35 publications

(35 citation statements)

References 40 publications

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“…In our study we compared the phenotype of cells expressing FIH-1 to that of cells where the expression was reduced by lentiviral transduction of shRNA directed against the enzyme. Using this approach we could not detect differences in proliferation of the cancer cell lines, although we observed an induction of p53 and p21, which was previously described by Pelletier et al to be accompanied by reduced proliferation in different wild-type p53 cell lines (Pelletier et al, 2012). Moreover, we were not able to detect differences in the interaction of ASPP2 and p53 or an effect on adhesion or migration of the cells in the presence or absence of FIH-1.…”

Section: Discussionmentioning

confidence: 32%

Factor Inhibiting HIF-1 (FIH-1) modulates protein interactions of Apoptosis-Stimulating p53 binding Protein 2 (ASPP2)

Janke

Brockmeier

Kuhlmann

et al. 2013

Journal of Cell Science

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SummaryThe asparaginyl hydroxylase factor inhibiting HIF-1 (FIH-1) is an important suppressor of hypoxia-inducible factor (HIF) activity. In addition to HIF-a, FIH-1 was previously shown to hydroxylate other substrates within a highly conserved protein interaction domain, termed the ankyrin repeat domain (ARD). However, to date, the biological role of FIH-1-dependent ARD hydroxylation could not be clarified for any ARD-containing substrate. The apoptosis-stimulating p53-binding protein (ASPP) family members were initially identified as highly conserved regulators of the tumour suppressor p53. In addition, ASPP2 was shown to be important for the regulation of cell polarity through interaction with partitioning defective 3 homolog (Par-3). Using mass spectrometry we identified ASPP2 as a new substrate of FIH-1 but inhibitory ASPP (iASPP) was not hydroxylated. We demonstrated that ASPP2 asparagine 986 (N986) is a single hydroxylation site located within the ARD. ASPP2 protein levels and stability were not affected by depletion or inhibition of FIH-1. However, FIH-1 depletion did lead to impaired binding of Par-3 to ASPP2 while the interaction between ASPP2 and p53, apoptosis and proliferation of the cancer cells were not affected. Depletion of FIH-1 and incubation with the hydroxylase inhibitor dimethyloxalylglycine (DMOG) resulted in relocation of ASPP2 from cell-cell contacts to the cytosol. Our data thus demonstrate that protein interactions of ARD-containing substrates can be modified by FIH-1-dependent hydroxylation. The large cellular pool of ARDcontaining proteins suggests that FIH-1 can affect a broad range of cellular functions and signalling pathways under certain conditions, for example, in response to severe hypoxia.

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Section: Discussionmentioning

confidence: 32%

Factor Inhibiting HIF-1 (FIH-1) modulates protein interactions of Apoptosis-Stimulating p53 binding Protein 2 (ASPP2)

Janke

Brockmeier

Kuhlmann

et al. 2013

Journal of Cell Science

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“…S2). Recently, FIH was shown to enhance in vitro proliferation of LS174 colon adenocarcinoma and A375 melanoma cells (25). Our work shows a unique function for FIH-1 in the positive regulation of keratinocyte proliferation.…”

Section: Fih-1 Expression Is Elevated In Conditions Of Abnormal Epithmentioning

confidence: 80%

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

Han¹,

Kaplan²,

Hamanaka

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

119

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Notch plays a critical role in the transition from proliferation to differentiation in the epidermis and corneal epithelium. Furthermore, aberrant Notch signaling is a feature of diseases like psoriasis, eczema, nonmelanoma skin cancer, and melanoma where differentiation and proliferation are impaired. Whereas much is known about the downstream events following Notch signaling, factors responsible for negatively regulating Notch receptor signaling after ligand activation are incompletely understood. Notch can undergo hydroxylation by factor-inhibiting hypoxia-inducible factor 1 (FIH-1); however, the biological significance of this phenomenon is unclear. Here we show that FIH-1 expression is upregulated in diseased epidermis and corneal epithelium. Elevating FIH-1 levels in primary human epidermal keratinocytes (HEKs) and human corneal epithelial keratinocytes (HCEKs) impairs differentiation in submerged cultures and in a "three-dimensional" organotypic raft model of human epidermis, in part, via a coordinate decrease in Notch signaling. Knockdown of FIH-1 enhances keratinocyte differentiation. Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium, resulting in a more differentiated phenotype. microRNA-31 (miR-31) is an endogenous negative regulator of FIH-1 expression that results in keratinocyte differentiation, mediated by Notch activation. Ectopically expressing miR-31 in an undifferentiated corneal epithelial cell line promotes differentiation and recapitulates a corneal epithelium in a three-dimensional raft culture model. Our results define a previously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part, controlled through a miR-31/FIH-1 nexus.

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“…This suggested that BBR-induced p21 (CIP1/WAF1) was through p53-dependent pathway. P21 (CIP1/WAF1) is a direct target of p53 [36], thus, p53 mediated induction of p21 (CIP1/WAF1) at least contributed to the inhibitory effect of BBR on cell proliferation and cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

p38α MAPK-mediated induction and interaction of FOXO3a and p53 contribute to the inhibited-growth and induced-apoptosis of human lung adenocarcinoma cells by berberine

Zheng¹,

Tang²,

Wu³

et al. 2014

J Exp Clin Cancer Res

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BackgroundBerberine (BBR), a component from traditional Chinese medicine, has been shown to possess anti-tumor activity against a wide spectrum of cancer cells including human lung cancer, but the detailed mechanism underlining this has not been well elucidated.MethodsIn this study, the effect of berberine on cell growth and apoptosis were assessed by MTT, flow cytometry and Hoechst 33258 staining assays. The phosphorylation of p38 MAPK and ERK1/2, and expressions of p38 MAPK isoforms α and β, total ERK1/2, p53, FOXO3a and p21 protein were evaluated by Western Blot analysis. Silencing of p38 MAPK isoform α and β, p53, FOXO3a and p21 were performed by siRNA methods. Exogenous expression of FOXO3a was carried out by electroporated transfection assays.ResultsWe showed that BBR significantly inhibited growth and induced cell cycle arrest of non small cell lung cancer (NSCLC) cells in the G0/G1 phase in a dose-dependent manner. Furthermore, we found that BBR increased phosphorylation of p38 MAPK and ERK1/2 in a time-dependent and induced protein expression of tumor suppressor p53 and transcription factor FOXO3a in a dose-dependent fashion. The specific inhibitor of p38 MAPK (SB203580), and silencing of p38α MAPK by small interfering RNAs (siRNAs), but not ERK1/2 inhibitor (PD98059) blocked the stimulatory effects of BBR on protein expression of p53 and FOXO3a. Interestingly, inhibition of p53 using one specific inhibitor (Pifithrin-α) and silencing of p53 using siRNAs overcome the inhibitory effect of BBR on cell growth. Silencing of FOXO3a appeared to attenuate the effect of BBR on p53 expression, cell proliferation and apoptosis. Furthermore, BBR induces the protein expression of cell cycle inhibitor p21 (CIP1/WAF1), which was not observed in cells silencing of p53 or FOXO3α gene. Intriguingly, exogenous expression of FOXO3a enhanced the expression of p21 (CIP1/WAF1) and strengthened BBR-induced apoptosis.ConclusionOur results show that BBR inhibits proliferation and induces apoptosis of NSCLC cells through activation of p38α MAPK signaling pathway, followed by induction of the protein expression of p53 and FOXO3a. The latter contribute to the BBR-increased p21 (CIP1/WAF1) protein expression. The exogenous FOXO3a, interaction and mutually exclusive events of p53 and FOXO3a augment the overall response of BBR.

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The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53–p21 axis

Cited by 35 publications

References 40 publications

Factor Inhibiting HIF-1 (FIH-1) modulates protein interactions of Apoptosis-Stimulating p53 binding Protein 2 (ASPP2)

Factor Inhibiting HIF-1 (FIH-1) modulates protein interactions of Apoptosis-Stimulating p53 binding Protein 2 (ASPP2)

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

p38α MAPK-mediated induction and interaction of FOXO3a and p53 contribute to the inhibited-growth and induced-apoptosis of human lung adenocarcinoma cells by berberine

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