A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

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.

[1]  N. Socci,et al.  Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. , 2003, Molecular cell.

[2]  W. Kaelin,et al.  Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth , 2003, PLoS biology.

[3]  Marjan S. Bolouri,et al.  Integrated Analysis of Protein Composition, Tissue Diversity, and Gene Regulation in Mouse Mitochondria , 2003, Cell.

[4]  B. Ackrell.  Progress in understanding structure–function relationships in respiratory chain complex II , 2000, FEBS letters.

[5]  P. Hogendoorn,et al.  SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology , 2003, The Journal of pathology.

[6]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[7]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[8]  V. de Franciscis,et al.  Signaling through Ras Is Essential for retOncogene-induced Cell Differentiation in PC12 Cells* , 2000, The Journal of Biological Chemistry.

[9]  Kan Ding,et al.  Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice , 2003, Nature Genetics.

[10]  W. Kaelin,et al.  The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. , 2003, Journal of the American Society of Nephrology : JASN.

[11]  S. Chew,et al.  Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. , 1995, Journal of medical genetics.

[12]  G. Semenza.  Signal transduction to hypoxia-inducible factor 1. , 2002, Biochemical pharmacology.

[13]  K. Nathanson,et al.  Pheochromocytoma: the expanding genetic differential diagnosis. , 2003, Journal of the National Cancer Institute.

[14]  S. Iwata,et al.  Architecture of Succinate Dehydrogenase and Reactive Oxygen Species Generation , 2003, Science.

[15]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[16]  George M. Hilliard,et al.  Cobalt Inhibits the Interaction between Hypoxia-inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia-inducible Factor-α* , 2003, The Journal of Biological Chemistry.

[17]  P. Rustin,et al.  The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. , 2001, American journal of human genetics.

[18]  B. Lemire,et al.  The Ubiquinone-binding Site of the Saccharomyces cerevisiae Succinate-Ubiquinone Oxidoreductase Is a Source of Superoxide* , 2003, Journal of Biological Chemistry.

[19]  E S Husebye,et al.  Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. , 2001, American journal of human genetics.

[20]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  C. Li,et al.  Feature extraction and normalization algorithms for high‐density oligonucleotide gene expression array data , 2001, Journal of cellular biochemistry. Supplement.

[22]  J. Mesirov,et al.  An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis , 2005, Nature Genetics.

[23]  M. Ivan,et al.  von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. , 2001, Human molecular genetics.

[24]  M. Wigler,et al.  The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins , 1990, Cell.

[25]  P. Ratcliffe,et al.  Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. , 2001, Human molecular genetics.

[26]  B. Devlin,et al.  Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. , 2000, Science.

[27]  P. Rustin,et al.  Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. , 2003, Cancer research.

[28]  A. Tischler,et al.  Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice , 2000, Cell and Tissue Research.

[29]  L. Aaltonen,et al.  Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. , 2004, American journal of human genetics.

[30]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[31]  J. Ritz,et al.  PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. , 1999, Human molecular genetics.

[32]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[33]  W. Kaelin,et al.  Molecular basis of the VHL hereditary cancer syndrome , 2002, Nature Reviews Cancer.

[34]  Mirna Lechpammer,et al.  Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. , 2002, Cancer cell.

[35]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  P. Rustin,et al.  Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. , 2002, The Journal of clinical endocrinology and metabolism.

[37]  Michio Tsuda,et al.  A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes , 1998, Nature.

[38]  Okio Hino,et al.  A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis. , 2005, Cancer research.

[39]  P. Ratcliffe,et al.  Independent function of two destruction domains in hypoxia‐inducible factor‐α chains activated by prolyl hydroxylation , 2001, The EMBO journal.

[40]  R. Aguiar,et al.  Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. , 2001, The Journal of clinical endocrinology and metabolism.

[41]  Shridar Ganesan,et al.  Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. , 2005, Genes & development.

[42]  E. Lander,et al.  MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia , 2002, Nature Genetics.