Characterization of the Activation of Protein Tyrosine Phosphatase, Receptor-Type, Z Polypeptide 1 (PTPRZ1) by Hypoxia Inducible Factor-2 Alpha

Wang, Victoria; Davis, David A.; Ravindra, P. V.; Haque, Muzammel; Yarchoan, Robert

doi:10.1371/journal.pone.0009641

Cited by 29 publications

(35 citation statements)

References 45 publications

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“…Target gene specificity in this case likely arises from additional trans-acting factors and/or cis-regulatory elements that cooperate specifically with HIF-2a. In a variety of HIF-2a-selective promoters (including the WISP2 promoter) HREs have previously been reported to cooperate with ETS-family transcription factor-binding sites (Elvert et al, 2003;Aprelikova et al, 2006;Hu et al, 2007;Le Bras et al, 2007;Wang et al, 2010), and HIF-2a has been shown to physically interact with ETS-1 and ELK-1 (Elvert et al, 2003;Aprelikova et al, 2006). Other HIF-2a-regulated genes at least contained one consensus HRE (Covello et al, 2006;Yamashita et al, 2008;Yang et al, 2010), although the stringency with which the core HRE has been determined was sometimes lowered to only half-sites of the 5 0 -RCGTG-3 0 motif (Saito et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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“…The expression plasmid encoding degradation-resistant forms of hypoxia-inducible factor-1␣ (HIF-1␣) (pcDNA-HIF-1␣m with substitutions P402A and P564A in HIF-1␣) has been described previously (10,41). An expression plasmid encoding KSHV RTA (pcDNA-RTA) was a gift from Keiji Ueda (Osaka University Graduate School of Medicine, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…In experiments to assess the response of the vIL-6 promoter to HIF-1␣ or HIF-2␣, a PTPRZ-1 reporter plasmid that was previously shown to be responsive to HIF-2␣ and, to a lesser extent, to HIF-1␣ (41) was used as a control. The HIF plasmids utilized encode HIF with mutagenized prolines that are not resistant to hydroxylation and degradation under normoxic conditions (41); the degradation-resistant HIF-1␣ plasmid was a gift of L. Eric Huang, previously of the NCI (44). The amount of each expression plasmid DNA used was as follows: pcDNA-XBP1u, 100 ng/well; pcDNAXBP1s, 100 ng/well; pcDNA-RTA, 250 ng/well; pcDNA degradation-resistant HIF-1␣ or HIF-2␣, 250 ng/well.…”

Section: Methodsmentioning

confidence: 99%

“…To explore whether HIF could directly activate vIL-6, we cotransfected degradation-resistant HIF-1␣ or HIF-2␣ with the vIL-6 reporter constructs pvIL6-1 (1,696 bp) or the mutant constructs. As a control, we utilized a PTPRZ-1 reporter construct that has previously been shown to respond to HIF-2␣ and, to a lesser extent, to HIF-1␣ (41). As seen in the results shown in Fig.…”

Section: Fig 2 Schematic Of Vil-6 Luciferase (Luc) Promoter and Constmentioning

confidence: 99%

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Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1

Wang

Yang

et al. 2016

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman disease (MCD). The KSHV life cycle has two principal gene repertoires, latent and lytic. KSHV viral interleukin-6 (vIL-6), an analog of human IL-6, is usually lytic; production of vIL-6 by involved plasmablasts is a central feature of KSHV-MCD. vIL-6 also plays a role in PEL and KS. We show that a number of plasmablasts from lymph nodes of patients with KSHV-MCD express vIL-6 but not ORF45, a KSHV lytic gene. We further show that vIL-6 is directly induced by the spliced (active) X-box binding protein-1 (XBP-1s), a transcription factor activated by endoplasmic reticulum (ER) stress and differentiation of B cells in lymph nodes. The promoter region of vIL-6 contains several potential XBP-response elements (XREs), and two of these elements in particular mediate the effect of XBP-1s. Mutation of these elements abrogates the response to XBP-1s but not to the KSHV replication and transcription activator (RTA). Also, XBP-1s binds to the vIL-6 promoter in the region of these XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce vIL-6. Patient-derived PEL tumor cells that produce vIL-6 frequently coexpress XBP-1, and immunofluorescence staining of involved KSHV-MCD lymph nodes reveals that most plasmablasts expressing vIL-6 also coexpress XBP-1. These results provide evidence that XBP-1s is a direct activator of KSHV vIL-6 and that this is an important step in the pathogenesis of KSHV-MCD and PEL. IMPORTANCE Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD)is characterized by severe inflammatory symptoms caused by an excess of cytokines, particularly KSHV-encoded viral interleukin-6 (vIL-6) produced by lymph node plasmablasts. vIL-6 is usually a lytic gene. We show that a number of KSHV-MCD lymph node plasmablasts express vIL-6 but do not have full lytic KSHV replication. Differentiating lymph node B cells express spliced (active) X-box binding protein-1 (XBP-1s). We show that XBP-1s binds to the promoter of vIL-6 and can directly induce production of vIL-6 through X-box protein response elements on the vIL-6 promoter region. We further show that chemical inducers of XBP-1s can upregulate production of vIL-6. Finally, we show that most vIL-6-producing plasmablasts from lymph nodes of KSHV-MCD patients coexpress XBP-1s. These results demonstrate that XBP-1s can directly induce vIL-6 and provide evidence that this is a key step in the pathogenesis of KSHV-MCD and other KSHV-induced diseases.

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“…Expression plasmids encoding degradationresistant forms of HIF-1␣ (pcDNA-HIF-1␣m) (P402A, P564A), as well as HIF-2␣ (pcDNA-HIF-2␣m) (P405A, P531A), which replace two prolines with alanines in the oxygen-dependent degradation domain of HIF-1␣ and HIF-2␣, have been described previously (17,49). An expression plasmid encoding KSHV RTA (pcDNA-RTA) (a kind gift from Keiji Ueda, Osaka University Graduate School of Medicine, Osaka, Japan) and pcDNA3.1 empty vector were used in cotransfection experiments.…”

Section: Methodsmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Induction by Hypoxia and Hypoxia-Inducible Factors

Ravindra

Haque

Davis

et al. 2012

J Virol

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Hypoxia and hypoxia-inducible factors (HIFs) play an important role in the Kaposi's sarcoma-associated herpesvirus (KSHV) life cycle. In particular, hypoxia can activate lytic replication of KSHV and specific lytic genes, including the replication and transcription activator (RTA), while KSHV infection in turn can increase the levels and activity of HIFs. In the present study, we show that hypoxia increases the levels of mRNAs encoding KSHV latency-associated nuclear antigen (LANA) in primary effusion lymphoma (PEL) cell lines and also increases the levels of LANA protein. Luciferase reporter assays in Hep3B cells revealed a moderate activation of the LANA promoter region by hypoxia as well as by cotransfection with degradation-resistant HIF-1␣ or HIF-2␣ expression plasmids. Computer analysis of a 1.2-kb sequence upstream of the LANA translational start site identified six potential hypoxia-responsive elements (HRE). Sequential deletion studies revealed that much of this activity was mediated by one of these HREs (HRE 4R) oriented in the 3= to 5= direction and located between the constitutive (LTc) and RTA-inducible (LTi) mRNA start sites. Site-directed mutation of this HRE substantially reduced the response to both HIF-1␣ and HIF-2␣ in a luciferase reporter assay. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated binding of both HIF-1␣ and HIF-2␣ to this region. Also, HIF-1␣ was found to associate with RTA, and HIFs enhanced the activation of LTi by RTA. These results provide evidence that hypoxia and HIFs upregulate both latent and lytic KSHV replication and play a central role in the life cycle of this virus.

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Characterization of the Activation of Protein Tyrosine Phosphatase, Receptor-Type, Z Polypeptide 1 (PTPRZ1) by Hypoxia Inducible Factor-2 Alpha

Cited by 29 publications

References 45 publications

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1

Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Induction by Hypoxia and Hypoxia-Inducible Factors

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