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Corine Bertolotto - One of the best experts on this subject based on the ideXlab platform.
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Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells.
Journal of Cell Biology, 2005Co-Authors: Roser Buscà, Edurne Berra, Cédric Gaggioli, Mehdi Khaled, Karine Bille, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Lionel Larribère, Corine BertolottoAbstract:In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates HIF1A gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1Alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the HIF1A promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on HIF1A expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that HIF1A is a new MITF target gene and that MITF mediates the cAMP stimulation of HIF1A in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1Alpha as a target, might contribute to melanoma progression.
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hypoxia inducible factor 1α is a new target of microphthalmia associated transcription factor mitf in melanoma cells
Journal of Cell Biology, 2005Co-Authors: Roser Buscà, Edurne Berra, Cédric Gaggioli, Mehdi Khaled, Karine Bille, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Lionel Larribère, Corine BertolottoAbstract:In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates HIF1A gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1Alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the HIF1A promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on HIF1A expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that HIF1A is a new MITF target gene and that MITF mediates the cAMP stimulation of HIF1A in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1Alpha as a target, might contribute to melanoma progression.
Adrian L Harris - One of the best experts on this subject based on the ideXlab platform.
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relation of hypoxia inducible factor 1α and 2α in operable non small cell lung cancer to angiogenic molecular profile of tumours and survival
British Journal of Cancer, 2001Co-Authors: Alexandra Giatromanolaki, M I Koukourakis, Efthimios Sivridis, Helen Turley, Kate L Talks, Francesco Pezzella, K C Gatter, Adrian L HarrisAbstract:Hypoxia inducible factors HIF1α and HIF2α are important proteins involved in the regulation of the transcription of a variety of genes related to erythropoiesis, glycolysis and angiogenesis. Hypoxic stimulation results in rapid increase of the HIF1α and 2α protein levels, as a consequence of a redox-sensitive stabilization. The HIFαs enter the nucleus, heterodimerize with the HIF1β protein, and bind to DNA at the hypoxia response elements (HREs) of target genes. In this study we evaluated the immunohistochemical expression of these proteins in 108 tissue samples from non-small-cell lung cancer (NSCLC) and in normal lung tissues. Both proteins showed a mixed cytoplasmic/nuclear pattern of expression in cancer cells, tumoural vessels and tumour-infiltrating macrophages, as well as in areas of metaplasia, while normal lung components showed negative or very weak cytoplasmic staining. Positive HIF1α and HIF2α expression was noted in 68/108 (62%) and in 54/108 (50%) of cases respectively. Correlation analysis of HIF2α expression with HIF1α expression showed a significant association (P < 0.0001, r = 0.44). A strong association of the expression of both proteins with the angiogenic factors VEGF (P < 0.004), PD-ECGF (P < 0.003) and bFGF (P < 0.04) was noted. HIF1α correlated with the expression of bek-bFGF receptor expression (P = 0.01), while HIF2α was associated with intense VEGF/KDR-activated vascularization (P = 0.002). HIF2α protein was less frequently expressed in cases with a medium microvessel density (MVD); a high rate of expression was noted in cases with both low and high MVD (P = 0.006). Analysis of overall survival showed that HIF2α expression was related to poor outcome (P = 0.008), even in the group of patients with low MVD (P = 0.009). HIF1α expression was marginally associated with poor prognosis (P = 0.08). In multivariate analysis HIF2α expression was an independent prognostic indicator (P = 0.006, t-ratio 2.7). We conclude that HIF1α and HIF2α overexpression is a common event in NSCLC, which is related to the up-regulation of various angiogenic factors and with poor prognosis. Targeting the HIF pathway may prove of importance in the treatment of NSCLC. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
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relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non small cell lung cancer to angiogenic molecular profile of tumours and survival
British Journal of Cancer, 2001Co-Authors: Alexandra Giatromanolaki, M I Koukourakis, Efthimios Sivridis, Helen Turley, Kate L Talks, Francesco Pezzella, K C Gatter, Adrian L HarrisAbstract:Hypoxia inducible factors HIF1α and HIF2α are important proteins involved in the regulation of the transcription of a variety of genes related to erythropoiesis, glycolysis and angiogenesis. Hypoxic stimulation results in rapid increase of the HIF1α and 2α protein levels, as a consequence of a redox-sensitive stabilization. The HIFαs enter the nucleus, heterodimerize with the HIF1β protein, and bind to DNA at the hypoxia response elements (HREs) of target genes. In this study we evaluated the immunohistochemical expression of these proteins in 108 tissue samples from non-small-cell lung cancer (NSCLC) and in normal lung tissues. Both proteins showed a mixed cytoplasmic/nuclear pattern of expression in cancer cells, tumoural vessels and tumour-infiltrating macrophages, as well as in areas of metaplasia, while normal lung components showed negative or very weak cytoplasmic staining. Positive HIF1α and HIF2α expression was noted in 68/108 (62%) and in 54/108 (50%) of cases respectively. Correlation analysis of HIF2α expression with HIF1α expression showed a significant association (P < 0.0001, r = 0.44). A strong association of the expression of both proteins with the angiogenic factors VEGF (P < 0.004), PD-ECGF (P < 0.003) and bFGF (P < 0.04) was noted. HIF1α correlated with the expression of bek-bFGF receptor expression (P = 0.01), while HIF2α was associated with intense VEGF/KDR-activated vascularization (P = 0.002). HIF2α protein was less frequently expressed in cases with a medium microvessel density (MVD); a high rate of expression was noted in cases with both low and high MVD (P = 0.006). Analysis of overall survival showed that HIF2α expression was related to poor outcome (P = 0.008), even in the group of patients with low MVD (P = 0.009). HIF1α expression was marginally associated with poor prognosis (P = 0.08). In multivariate analysis HIF2α expression was an independent prognostic indicator (P = 0.006, t-ratio 2.7). We conclude that HIF1α and HIF2α overexpression is a common event in NSCLC, which is related to the up-regulation of various angiogenic factors and with poor prognosis. Targeting the HIF pathway may prove of importance in the treatment of NSCLC. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
Edurne Berra - One of the best experts on this subject based on the ideXlab platform.
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PHD3–SUMO conjugation represses HIF1 transcriptional activity independently of PHD3 catalytic activity
Journal of Cell Science, 2014Co-Authors: Analía Núñez-o'mara, Fernando Lopitz-otsoa, Almudena Gerpe-pita, Sara Pozo, Onintza Carlevaris, Bakarne Urzelai, Manuel S. Rodriguez, Edurne BerraAbstract:ABSTRACT By controlling HIFα hydroxylation and stability, the prolyl hydroxylase domain (PHD)-containing proteins are essential to the maintenance of oxygen homeostasis; therefore these enzymes are tightly regulated. Small ubiquitin-like modifier (SUMO) is a 10-kDa protein readily conjugated to lysine residues of the targeted proteins in a process termed SUMOylation. In this study, we introduce SUMO conjugation as a novel regulator of PHD3 (also known as EGLN3). PHD3 SUMOylation occurs at a cluster of four lysines at the C-terminal end of the protein. Furthermore, PHD3 SUMOylation by SUMO2 or SUMO3 contributes to PHD3-mediated repression of HIF1-dependent transcriptional activity. Interestingly, PHD3–SUMO conjugation does not affect PHD3 hydroxylase activity or HIF1α stability, providing new evidence for a dual role of PHD3 in HIF1 regulation. Moreover, we show that hypoxia modulates PHD3–SUMO conjugation and that this modification inversely correlates with HIF1 activation. PHD3 SUMOylation highlights a new and additional layer of regulation that is likely required to fine-tune HIF function.
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Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells.
Journal of Cell Biology, 2005Co-Authors: Roser Buscà, Edurne Berra, Cédric Gaggioli, Mehdi Khaled, Karine Bille, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Lionel Larribère, Corine BertolottoAbstract:In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates HIF1A gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1Alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the HIF1A promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on HIF1A expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that HIF1A is a new MITF target gene and that MITF mediates the cAMP stimulation of HIF1A in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1Alpha as a target, might contribute to melanoma progression.
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hypoxia inducible factor 1α is a new target of microphthalmia associated transcription factor mitf in melanoma cells
Journal of Cell Biology, 2005Co-Authors: Roser Buscà, Edurne Berra, Cédric Gaggioli, Mehdi Khaled, Karine Bille, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Lionel Larribère, Corine BertolottoAbstract:In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates HIF1A gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1Alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the HIF1A promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on HIF1A expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that HIF1A is a new MITF target gene and that MITF mediates the cAMP stimulation of HIF1A in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1Alpha as a target, might contribute to melanoma progression.
Roser Buscà - One of the best experts on this subject based on the ideXlab platform.
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Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells.
Journal of Cell Biology, 2005Co-Authors: Roser Buscà, Edurne Berra, Cédric Gaggioli, Mehdi Khaled, Karine Bille, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Lionel Larribère, Corine BertolottoAbstract:In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates HIF1A gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1Alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the HIF1A promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on HIF1A expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that HIF1A is a new MITF target gene and that MITF mediates the cAMP stimulation of HIF1A in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1Alpha as a target, might contribute to melanoma progression.
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hypoxia inducible factor 1α is a new target of microphthalmia associated transcription factor mitf in melanoma cells
Journal of Cell Biology, 2005Co-Authors: Roser Buscà, Edurne Berra, Cédric Gaggioli, Mehdi Khaled, Karine Bille, Barbara Marchetti, Raphaël Thyss, Giorgos Fitsialos, Lionel Larribère, Corine BertolottoAbstract:In melanocytes and melanoma cells alpha-melanocyte stimulating hormone (alpha-MSH), via the cAMP pathway, elicits a large array of biological responses that control melanocyte differentiation and influence melanoma development or susceptibility. In this work, we show that cAMP transcriptionally activates HIF1A gene in a melanocyte cell-specific manner and increases the expression of a functional hypoxia-inducible factor 1alpha (HIF1Alpha) protein resulting in a stimulation of Vegf expression. Interestingly, we report that the melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the HIF1A promoter and strongly stimulates its transcriptional activity. Further, MITF "silencing" abrogates the cAMP effect on HIF1A expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA. Our data demonstrate that HIF1A is a new MITF target gene and that MITF mediates the cAMP stimulation of HIF1A in melanocytes and melanoma cells. Importantly, we provide results demonstrating that HIF1 plays a pro-survival role in this cell system. We therefore conclude that the alpha-MSH/cAMP pathway, using MITF as a signal transducer and HIF1Alpha as a target, might contribute to melanoma progression.
Xiaosheng Wang - One of the best experts on this subject based on the ideXlab platform.
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HIF1A expression correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers.
Cellular Oncology, 2020Co-Authors: Baotao Chen, Xiaosheng WangAbstract:Background Although many studies have revealed essential roles of HIF1A (hypoxia inducible factor 1 subunit alpha) in regulating various pathways associated with cancer development, a systematic investigation of associations of HIF1A expression with tumor immunity, the tumor microenvironment and other tumor phenotypes in pan-cancer is lacking. Methods Using cancer genomics datasets of 10 cancer cohorts from the Cancer Genome Atlas (TCGA) program, we investigated associations of HIF1A expression with tumor immune and stromal signatures, and various tumor phenotypes, including cell proliferation, stemness, epithelial-mesenchymal transition (EMT), tumor purity, oncogenic signaling, and clinical outcomes. Results HIF1A upregulation was found to be associated with increased immune and stromal signatures, aggressive phenotypes, and worse survival rates in various cancers. Moreover, HIF1A upregulation was not only associated with activation of various oncogenic signaling pathways, but also with increased tumor suppressive signatures, including apoptosis and anti-tumor immune response, indicative of a dual role of HIF1A in cancer development. However, HIF1A expression showed a stronger correlation with immune-inhibiting signatures than with immune-promoting signatures. Furthermore, HIF1A expression was found to be positively associated with both tumor immune infiltration and PD-L1 expression, indicating that tumors with elevated expression of HIF1A may exhibit a more active immunotherapy response. This indication was substantiated in a kidney cancer cohort receiving anti-PD-1/PD-L1 immunotherapy. Conclusions HIF1A upregulation correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers. Our analysis may provide new insights into the role of HIF1A in tumor biology and clinical management.
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HIF1A expression correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers.
Cellular oncology (Dordrecht), 2020Co-Authors: Baotao Chen, Xiaosheng WangAbstract:Although many studies have revealed essential roles of HIF1A (hypoxia inducible factor 1 subunit alpha) in regulating various pathways associated with cancer development, a systematic investigation of associations of HIF1A expression with tumor immunity, the tumor microenvironment and other tumor phenotypes in pan-cancer is lacking. Using cancer genomics datasets of 10 cancer cohorts from the Cancer Genome Atlas (TCGA) program, we investigated associations of HIF1A expression with tumor immune and stromal signatures, and various tumor phenotypes, including cell proliferation, stemness, epithelial-mesenchymal transition (EMT), tumor purity, oncogenic signaling, and clinical outcomes. HIF1A upregulation was found to be associated with increased immune and stromal signatures, aggressive phenotypes, and worse survival rates in various cancers. Moreover, HIF1A upregulation was not only associated with activation of various oncogenic signaling pathways, but also with increased tumor suppressive signatures, including apoptosis and anti-tumor immune response, indicative of a dual role of HIF1A in cancer development. However, HIF1A expression showed a stronger correlation with immune-inhibiting signatures than with immune-promoting signatures. Furthermore, HIF1A expression was found to be positively associated with both tumor immune infiltration and PD-L1 expression, indicating that tumors with elevated expression of HIF1A may exhibit a more active immunotherapy response. This indication was substantiated in a kidney cancer cohort receiving anti-PD-1/PD-L1 immunotherapy. HIF1A upregulation correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers. Our analysis may provide new insights into the role of HIF1A in tumor biology and clinical management.