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      A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

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          Abstract

          Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions . We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors.

          Synopsis

          Pheochromocytomas (also known as paragangliomas) are highly vascular tumors that arise from mutations in a diverse and apparently unrelated group of tumor suppressor genes and oncogenes. The authors show here that three of the genes that cause hereditary pheochromocytomas have a common function. Specifically, these genes, VHL, SDHB, and SDHD, encode proteins that regulate a transcription factor known as hypoxia-inducible factor 1 subunit α (HIF1α), which helps cells adapt to hypoxia (low oxygen levels). VHL is named after its role in von Hippel-Lindau disease (VHL), an inherited disorder that predisposes individuals to pheochromocytomas and other tumors. Previous studies showed that when cells lack VHL, HIF1α is not degraded, resulting in a signal that resembles hypoxia. The authors found that loss of two genes that cause two distinct pheochromocytoma syndromes (the genes SDHB and SDHD, which encode the subunits B and D of succinate dehydrogenase, a component enzyme of the energy and respiratory system in mitochondria) also triggers a HIF1α response. The researchers further discovered that high H1F1α levels can suppress SDHB. This suggests a regulatory loop that further enhances the “hypoxia” profile of tumors. This finding provides a rational explanation for the shared features of these distinct syndromes and may be relevant for other cancers with a prominent hypoxic pattern.

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          Most cited references 38

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          Cluster analysis and display of genome-wide expression patterns.

          A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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            HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

             M Ivan,  Theresa Kim,  A Salic (2001)
            HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.
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              Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection.

              Recent advances in cDNA and oligonucleotide DNA arrays have made it possible to measure the abundance of mRNA transcripts for many genes simultaneously. The analysis of such experiments is nontrivial because of large data size and many levels of variation introduced at different stages of the experiments. The analysis is further complicated by the large differences that may exist among different probes used to interrogate the same gene. However, an attractive feature of high-density oligonucleotide arrays such as those produced by photolithography and inkjet technology is the standardization of chip manufacturing and hybridization process. As a result, probe-specific biases, although significant, are highly reproducible and predictable, and their adverse effect can be reduced by proper modeling and analysis methods. Here, we propose a statistical model for the probe-level data, and develop model-based estimates for gene expression indexes. We also present model-based methods for identifying and handling cross-hybridizing probes and contaminating array regions. Applications of these results will be presented elsewhere.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                pgen
                PLoS Genetics
                1553-7390
                1553-7404
                July 2005
                25 July 2005
                : 1
                : 1
                Affiliations
                [1 ] Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ] Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
                [3 ] University of São Paulo School of Medicine, São Paulo, Brazil
                [4 ] Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [5 ] Center of Endocrine Investigations, Hospital de Niños R. Gutierrez, Buenos Aires, Argentina
                [6 ] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
                [7 ] Tufts–New England Medical Center, Boston, Massachusetts, United States of America
                [8 ] Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [9 ] Yale University, New Haven, Connecticut, United States of America
                [10 ] Royal North Shore Hospital and Kolling Institute of Medical Research, University of Sydney, Australia
                [11 ] Division of Population Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
                [12 ] Boston Medical Center, Boston, Massachusetts, United States of America
                [13 ] St. Bartholomew's Hospital, London, United Kingdom
                [14 ] Regional University Hospital, Lille, France
                [15 ] Department of Biostatistical Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
                The Jackson Laboratory, United States of America
                Author notes
                *To whom correspondence should be addressed. E-mail: Patricia_Dahia@ 123456dfci.harvard.edu

                ¤Current address: Department of Medicine and Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, United States of America

                Article
                05-PLGE-RA-0034R3 plge-01-01-11
                10.1371/journal.pgen.0010008
                1183527
                16103922
                Copyright: © 2005 Dahia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
                Categories
                Research Article
                Bioinformatics - Computational Biology
                Cancer Biology
                Cell Biology
                Diabetes - Endocrinology - Metabolism
                Molecular Biology - Structural Biology
                Pathology
                Genetics/Genomics
                Genetics/Genetics of Disease
                Genetics/Disease Models
                Genetics/Gene Expression
                Homo (Human)
                In Vitro
                Custom metadata
                Dahia PLM, Ross KN, Wright ME, Hayashida CY, Santagata S, et al. (2005) A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1(1): e8.

                Genetics

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