Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor

Coleman, Mathew L.; McDonough, Michael A.; Hewitson, Kirsty S.; Coles, C.H.; Mecinović, Jasmin; Edelmann, Mariola J.; Cook, Kristina M.; Cockman, Matthew E.; Lancaster, David; Kessler, Benedikt M.; Oldham, Neil J.; Ratcliffe, Peter J.; Schofield, Christopher J.

doi:10.1074/jbc.m704102200

Cited by 198 publications

(258 citation statements)

References 32 publications

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“…These observations agree with a previous study suggesting that Notch signaling is increased in hypoxia through the direct interaction between the intracellular Notch receptor domain N ICD and HIF-1 (24). We speculate that increased N ICD levels through Jagged2 expression could reciprocally inhibit factor-inhibiting HIF (FIH) and augment HIF function to provide a hypoxic growth advantage independent of Notch target genes (30). Further evidence suggests that N ICD enhances HIF1 recruitment to its target gene promoters, resulting in increased HIF1 activity in vitro (23).…”

Section: High Myc State Increases Notch Signaling Components With Jagsupporting

confidence: 82%

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

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

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Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

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Section: High Myc State Increases Notch Signaling Components With Jagsupporting

confidence: 82%

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

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

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“…All these proteins contain ankyrin-repeat domains (ARDs) and include IkBa; p105; Notch1, 2 and 3; and Ankyrin repeat and SOCS Box protein 4 (ASB4). [44][45][46] Presently, the function of hydroxylation on these novel substrates remains unclear, with only subtle downstream effects, if any, being observed. However, it has been suggested that hydroxylation of ARD-containing proteins occurs in competition with HIF hydroxylation, and could potentially regulate HIF-mediated transcription by sequestering FIH-1, particularly in hypoxia.…”

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

confidence: 99%

“…However, it has been suggested that hydroxylation of ARD-containing proteins occurs in competition with HIF hydroxylation, and could potentially regulate HIF-mediated transcription by sequestering FIH-1, particularly in hypoxia. 45 …”

Section: Oxygen-dependent Regulation Of Hif-cad By Fih-1mentioning

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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“…Importantly, mass spectroscopic evidence for hydroxylation of ankyrin repeats in IkB and nuclear factor kB family members, as well as in ASB4, a suppressor of cytokine signaling, by FIH showed that hydroxylation is not restricted to HIF-a subunits (Coleman et al, 2007;Ferguson et al, 2007). Although direct mass spectroscopic evidence for hydroxylation is missing, PHD1 and PHD3 have recently been shown to regulate IkB kinase-b and activating transcription factor-4, respectively (Cummins et al, 2006;Koditz et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

Balamurugan

et al. 2009

Oncogene

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The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1a. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.

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Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor

Cited by 198 publications

References 32 publications

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Turn me on: regulating HIF transcriptional activity

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

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