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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 6 2890-2894
Copyright © 2001 by The Endocrine Society

Other Original Studies

Analysis of the SDHD Gene, the Susceptibility Gene for Familial Paraganglioma Syndrome (PGL1), in Pheochromocytomas1

Ricardo C. T. Aguiar2, Gerry Cox, Scott L. Pomeroy3 and Patricia L. M. Dahia3,4

Departments of Adult Oncology (R.C.T.A., P.L.M.D.) and Cancer Biology (P.L.M.D.), Dana-Farber Cancer Institute, and Departments of Genetics (G.C.) and Neurology (S.L.P.), Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115-6084

Address all correspondence and requests for reprints to: Patricia L. M. Dahia, Department of Cancer Biology/Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, SM1010, Boston, Massachusetts 02115-6084. E-mail: patricia_dahia{at}dfci.harvard.edu

Abstract

Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739A->G). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34–36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.

PHEOCHROMOCYTOMAS are rare neoplasms embryologically derived from the neural crest that occur mostly sporadically (1). In 10% of cases, pheochromocytomas are inherited as part of the multiple endocrine neoplasia type 2 syndrome (MEN 2A and 2B), von Hippel-Lindau (VHL) disease, and, rarely, neurofibromatosis type 1. Pheochromocytomas may also occur as an isolated familial form without other associated clinical features (2, 3). MEN 2A and MEN 2B are caused by germline mutations of the RET tyrosine kinase receptor (4), whereas VHL disease results from germline mutations of the VHL tumor suppressor gene (5). Somatic RET and VHL mutations are only rarely found in sporadic pheochromocytoma (6), suggesting that an additional gene(s) is involved in its pathogenesis.

Loss of heterozygosity (LOH) has been reported in several loci in pheochromocytomas: 1p34–36, which affects 25–70% of tumors (7, 8, 9, 10, 11); 3p24–25, seen in 20–40% of tumors (7, 9, 10); and 22q, which is seen in approximately 40% of the cases (7, 12). Less common sites of LOH in these tumors are 17p (7), 11q, and 11p (13). These loci might encompass a tumor suppressor gene(s) that may be involved in pheochromocytoma pathogenesis.

Nonchromaffin paragangliomas arising from the parasympathetic ganglia of the head and neck, in particular the carotid body (also known as chemodectomas), share a similar embryological origin with pheochromocytomas (14, 15, 16, 17). Recently, the SDHD gene was identified as a major susceptibility gene for the familial paraganglioma syndrome (PGL1), an autosomal dominant disorder with rare maternal transmission suggestive of imprinting (18). The SDHD gene encodes the succinate dehydrogenase subunit D gene (GenBank accession no. AB026906) representing the small subunit (cybS) of cytochrome b, which is a component of complex II of the mitochondrial respiratory chain (19). Mitochondrial complex II controls aerobic electron transport, which takes part on the regulation of oxygen sensing and signaling (20). It has been postulated that mutant cybS leads to cellular proliferation of paraganglionic tissue in response to chronic hypoxic stimulation resulting from its malfunction (18). Patients with PGL1 were found to have germline mutations of the SDHD gene, which are expected to disrupt the function of the protein, consistent with its role as a tumor suppressor. Nonsense and missense mutations were found in highly conserved regions of the SDHD gene in five PGL1 families (18). Despite its presumed maternal imprinting transmission, no evidence of germline imprinting of the SDHD gene was observed in the initially examined individuals.

The VHL protein has also been shown to be regulated by hypoxia (21). In the absence of functional VHL, a hypoxia-regulated transcription factor, hypoxia-inducible factor-1, is activated. As nonchromaffin paragangliomas are embryologically related to pheochromocytomas, and a hypoxia- mediated stimulus also appears to play a role in the pathogenesis of pheochromocytomas, in particular those associated with VHL syndrome, we tested the hypothesis that mutations in the SDHD gene are present in these tumors.

Materials and Methods

Samples

We studied 19 sporadic and 1 familial pheochromocytoma. Four of the sporadic tumors were malignant. Clinical data from the patients have been described previously (22). DNA from tumor and peripheral blood lymphocytes was prepared using standard protocols. Informed consent was obtained from all subjects and/or guardians involved in this study.

Ribonucleic acid was extracted from two pheochromocytomas using TRIzol (Life Technologies, Inc., Gaithersburg, MD), according to the manufacturer’s instructions and was reverse transcribed to complementary DNA (cDNA) with random primers, as previously described (23).

PCR, restriction digestions, and sequence analysis

Intronic primers flanking each one of the four SDHD gene exons were designed based on the published SDHD genomic sequence (GenBank accession no. AB026906) and were used for PCR (Table 1Go and Fig. 1AGo). Samples were subjected to 35 cycles of 1 min each at 94, 58, and 72 C, followed by a final extension step at 72 C for 10 min. PCR products were purified and sequenced as previously described (24).


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  		Table 1. Primers used in this study

 


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  		Figure 1. A, Comparison between the structures of SDHD and SDHDP1. Exons are shown as boxes; introns are shown as horizontal lines. {square}, Coding exons; {blacksquare}, 5'- and 3'UTRs. SDHDP1 differs from SDHD cDNA at the 5'UTR (except for the 13 nucleotides most proximal to the coding region, shown as the black portion of the box) and at six nucleotides (*) throughout the coding region. B, Comparison between SDHD and SDHDP1 at the amino acid level. Mismatches are underlined. Primers are shown as arrows (according to Table 1Go); those located above the gene are forward oligonucleotides, and those located below are reverse oligonucleotides.

 
All samples with sequence changes in relation to the original SDHD database entry were reamplified from genomic DNA and directly sequenced as described above. A sequence variant in amplicon 3 was further characterized in both tumor and germline DNA by restriction digestion with TaqI (see below), according to the manufacturer’s instructions (New England Biolabs, Inc., Beverly, MA).

An additional forward primer (5F) was used in combination with the SDHD/exon 4 reverse primer, 4R (Fig. 1AGo and Table 1Go), to generate a 585-bp amplicon specific to an SDHD cDNA homologous sequence located at chromosome 1p34–36. This sequence will be referred to hereafter as SDHDP1, in accordance with nomenclature guidelines proposed by the HUGO gene nomenclature committee (http://www.gene. ucl.ac.uk/nomenclature/guidelines.html). The specificity of this PCR is given by the forward primer (5F), which is unique to SDHDP1. All pheochromocytomas were amplified, and the products were purified and directly sequenced as above. Digestion of this amplicon with AvaI (New England Biolabs, Inc.), according to the manufacturer’s guidelines, yields two products of 302 and 283 bp.

RT-PCR

In addition to the primer combination above, another primer, 6F (Table 1Go), located downstream from 5F and mapping to the second exon of the SDHD gene (Fig. 1AGo), was used in combination with the 4R primer to determine whether SDHDP1 was expressed in two pheochromocytoma cDNAs. This primer combination would amplify a 416-bp product from both SDHD and SDHDP1 sequences. To ensure that the product generated was SDHD cDNA only and was not a combination of SDHD and SDHDP1, this resulting fragment was digested with AvaI (New England Biolabs, Inc.) according to the manufacturer’s guidelines. This enzyme recognizes a single site in SDHDP1, generating products of 302 and 114 bp, but does not cut the functional SDHD gene.

Somatic cell hybrid mapping of the SDHD homologous sequence

To confirm the location of the SDHDP1 sequence, a somatic cell hybrid panel generated using mouse and hamster backgrounds (UK Human Genome Mapping Project-HGMP-Resource Center, Cambridge, UK) was screened by PCR with primers specific to SDHDP1 (5F and 4R, Fig. 1AGo), using the conditions described above. PCR products were run on agarose gel, transferred to a nylon membrane, and hybridized to an internal oligonucleotide (6F), as previously described (25).

Results and Discussion

We did not find mutations of the SDHD gene in this series of 20 pheochromocytomas. Two single nucleotide polymorphisms were identified in the same 3 samples (15% of the cases): 1 is a novel variant, g.97739A->G (according to the reference sequence numbering on GenBank accession no. AB026906), and the other is c.204C->T (S68S), which has been previously described (18). Both variants could be distinguished by differential restriction digestion. The first variant, identified by amplicon 3 and located 29 nucleotides upstream of the start of exon 3, yielded 2 products of 223 and 70 bp after digestion with TaqI (data not shown). The second variant was previously identified and can be recognized by digestion with SpeI, as described (18). One of the three samples carrying both variants was from a malignant pheochromocytoma. These variants were present in both tumor and germline DNA, suggesting that they are probably polymorphisms. The frequency of the novel single nucleotide polymorphism is similar to that seen in an equal number of control chromosomes of an age- and ethnically matched population (data not shown).

While searching the GenBank database, we identified a highly homologous sequence of SDHD in 1p34–36, a region known to show high LOH rates in pheochromocytomas (7, 8, 10, 12). This SDHD-like sequence had been found previously in a genomic DNA library used to clone the SDHD gene (26). This sequence, SDHDP1, differs from the SDHD coding region at only six amino acids and maintains high homology across the 3'-untranslated region (UTR; Fig. 1BGo). However, the homologous sequence lacks the SDHD introns and diverges from SDHD in the 5'UTR, 13 bases upstream of the start codon. This sequence has features compatible with a processed pseudogene, i.e. it carries high homology with the cDNA sequence of a functional gene without its introns, but is found integrated into a distinct upstream context (27, 28, 29). Processed pseudogenes represent a fraction of the pseudogenes present in the mammalian genome and are believed to result mostly from retrotransposition followed by random integration into the genome (27, 28, 29, 30). Based on the GenBank annotation for this entry, SDHDP1 is located within the third intron of the RH blood group CE (RHCE) locus (GenBank accession no. AL031284) in chromosome 1p35–36.13. By using a somatic cell hybrid panel with primers designed to specifically recognize this sequence, we confirmed the location of SDHDP1 to chromosome 1 (Fig. 2Go).



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  		Figure 2. Confirmation of the SDHDP1 location in chromosome 1 by somatic cell hybrid mapping. A, PCR results of single human chromosomes as well as human, mouse, and hamster genomic DNA controls. B, Southern blot analysis of the PCR show in A hybridized with a specific internal oligonucleotide.

 
Alternatively, despite the features described above, this sequence could be a functional SDHD homolog. It has been proposed that as yet unidentified, additional functional SDHD homologs may account for the well recognized tissue specificity of cytochrome b (26, 31). Of note, six SDHD homologous sequences have been described that are distributed throughout the genome (26, 31). Five of these sequences are associated with multiple frame shifts, leading to premature stop codons in relation to the original SDHD active gene sequence and are therefore unlikely to have any functional properties; they are most probably pseudogenes (26). In contrast, the SDHD homolog in chromosome 1p34–36, an area of common LOH in pheochromocytomas, had only six nucleotide differences, all leading to six putative amino acid changes (L4P, L14Q, L77P, M91T, L120S, and L131F) in comparison with the functional SDHD gene (Fig. 1BGo). We therefore sought to verify whether the chromosome 1 SDHD-like sequence, SDHDP1, could represent a functional gene. We thus investigated whether SDHDP1 was transcribed and also examined its sequence in our series of pheochromocytomas. In addition to the already mentioned six nucleotide differences, we observed a heterozygous sequence variation in SDHDP1 in 70% (14 of 20) of our samples corresponding to g.29744C->T (numbered from the GenBank entry AL031284). This nucleotide substitution would not result in amino acid change (aspartic acid 113 in the original SDHD ORF). As this variation was also present in germline DNA, this change was not a somatic event. No other sequence variations of the SDHDP1 were seen in the samples examined.

To determine whether SDHDP1 was transcribed, we used cDNA from two sporadic pheochromocytomas as templates for PCRs. Using a SDHDP1-specific forward primer (5F) in combination with the reverse 4R primer, no product was amplified from cDNA; only genomic templates amplified the expected 585-bp amplicon (Fig. 3Go). To exclude the possibility that the unique forward sequence was untranscribed, we also used a downstream forward primer, 6F, which would recognize both SDHDP1 and functional SDHD sequences in an RT-PCR. These two sequences could be distinguished by differential restriction enzyme digestion, as only SDHDP1 is cut by AvaI. We did not observe any digested product from the pheochromocytoma cDNAs, which suggests that SDHDP1 is either not transcribed or is transcribed at very low levels in this tissue (Fig. 3Go). Our findings, therefore, suggest that this sequence is a processed pseudogene not expressed in pheochromocytomas. The common sequence variation that we observed may be the result of spontaneous mutation of the sequence that occurred evolutionarily after the divergence between the functional gene and SDHDP1. The existence of SDHD pseudogenes should thus be considered when analyzing cDNA-based samples, as sequence variations may confound the interpretation of the SDHD gene mutation analysis.



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  		Figure 3. Lack of SDHDP1 expression in pheochromocytoma cDNAs. Results from PCR using primers that span the coding region SDHD cDNA (6F and 4R, see Table 1Go) are displayed. Undigested and AvaI- digested cDNA products are shown in lanes 2, 3, and 4. Lane 5 is a control without DNA. SDHDP1-specific PCR products (using primers 5F and 4R) are shown in the subsequent lanes. Undigested and AvaI- digested genomic products are shown in lanes 6, 7, and 8. A negative control without DNA is shown in lane 9. AvaI specifically cuts SDHDP1, producing fragments of 302 and 283 bp, which are not resolved by a 1.5% agarose gel (see Materials and Methods for details).

 
It is interesting to note that both paragangliomas and VHL-related pheochromocytomas share a defect in the mechanism of the oxygen-sensing system. In response to hypoxia, there is an increased expression of genes involved in energy metabolism, angiogenesis, and apoptosis (32, 33, 34). High levels of hypoxia-inducible factor-1 are presumed to account for the high vascularization seen in VHL-related tumors (21). Both paragangliomas and pheochromocytomas are known to be highly vascular tumors. Similarly, it has been proposed that disruption of cytochrome b in mitochondrial complex II, which occurs in PGL1, may lead to chronic hypoxic stimulation that may trigger cellular proliferation of the paraganglionic tissue of the head and neck (18), although this hypothesis has yet to be proven experimentally. This common link between a defect in handling hypoxic stimuli and tumor development in these two neoplasms may have implications for the pathogenesis of other forms of pheochromocytomas. Although we did not find mutations of the major PGL1 susceptibility gene in pheochromocytomas, it is reasonable to speculate that genes encoding for products that take part in the oxygen signaling/sensing system might be putative candidate genes in the pathogenesis of these tumors.

Note Added in Proof

Since the submission of this manuscript, two other reports analyzed the role of SDHD in pheochromocytomas: Gimm et al. Cancer Res 2000; 60:6822-5 and Astuti et al.Lancet 2001; 357:1181-2.

Acknowledgments

We are grateful to Drs. Margaret Shipp, Charles Stiles, and Sérgio Toledo for their support, and to Dr. Charis Eng for her critical review of the manuscript.

Footnotes

1 This work was supported by NIH Grant -NS35701 and the Kyle Mullarkey Research Fund (to S.P.), and NIH Grant P30-HD-18655 (to the Mental Retardation Research Center Core DNA Sequencing Facility). Back

2 Special Fellow of the Leukemia and Lymphoma Society of America. Back

3 These authors contributed equally to this work. Back

4 Recipient of a Susan G. Komen Breast Cancer Research Foundation Fellowship (to C. Eng). Back

Received September 9, 2000.

Revised December 28, 2000.

Revised February 14, 2001.

Accepted February 28, 2001.

References

  1. Bravo EL, Gifford RW. 1984 Pheochromocytoma: diagnosis, localization and management. N Engl J Med. 30:1682–1686.
  2. Kalff V, Shapiro B, Lloyd R, Nakajo M, Sisson JC, Beierwaltes WH. 1984 Bilateral pheochromocytomas. J Endocrinol Invest. 7:387–392.[Medline]
  3. Irvin GLd, Fishman LM, Sher JA. 1983 Familial pheochromocytoma. Surgery. 94:938–940.[Medline]
  4. Mulligan LM, Kwok JBJ, Healey CS, et al. 1993 Germline mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 363:458–460.[CrossRef][Medline]
  5. Latif F, Tory K, Gnarra J, et al. 1993 Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 260:1317–1320.[Abstract/Free Full Text]
  6. Eng C, Crossey PA, Mulligan LM, et al. 1995 Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. J Med Genet. 32:934–937.[Abstract]
  7. Khosla S, Patel VM, Hay ID, et al. 1991 Loss of heterozygosity suggests multiple genetic alterations in pheochromocytomas and medullary thyroid carcinomas. J Clin Invest. 87:1691–1699.
  8. Moley JF, Brother MB, Fong CT, et al. 1992 Consistent association of 1p loss of heterozygosity with pheochromocytomas from patients with multiple endocrine neoplasia type 2 syndromes. Cancer Res. 52:770–774.[Abstract/Free Full Text]
  9. Zeiger MA, Zbar B, Keiser H, Linehan WM, Gnarra JR. 1995 Loss of heterozygosity on the short arm of chromosome 3 in sporadic, von Hippel-Lindau disease-associated, and familial pheochromocytoma. Genes Chromosomes Cancer. 13:151–156.[Medline]
  10. Vargas MP, Zhuang Z, Wang C, Vortmeyer A, Linehan WM, Merino MJ. 1997 Loss of heterozygosity on the short arm of chromosomes 1 and 3 in sporadic pheochromocytoma and extra-adrenal paraganglioma. Hum Pathol. 28:411–415.[CrossRef][Medline]
  11. Bender BU, Gutsche M, Gläsker S, et al. 2000 Differential genetic alterations in von Hippel-Lindau syndrome: associated and sporadic pheochromocytomas. J Clin Endocrinol Metab. 85:4568–4574.[Abstract/Free Full Text]
  12. Shin E, Fujita S, Takami K, et al. 1993 Deletion mapping of chromosome 1p and 22q in pheochromocytoma. Jpn J Cancer Res. 84:402–408.[CrossRef][Medline]
  13. Yokogoshi Y, Yoshimoto K, Saito S. 1990 Loss of heterozygosity on chromosomes 1 and 11 in sporadic pheochromocytomas. Jpn J Cancer Res. 81:632–638.[CrossRef][Medline]
  14. van Schothorst EM, Jansen JC, Bardoel AF, et al. 1996 Confinement of PGL, an imprinted gene causing hereditary paragangliomas, to a 2-cM interval on 11q22–q23 and exclusion of DRD2 and NCAM as candidate genes. Eur J Hum Genet. 4:267–273.[Medline]
  15. Baysal BE, Farr JE, Rubinstein WS, et al. 1997 Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas, on chromosome 11q23. Am J Hum Genet. 60:121–132.[Medline]
  16. Heutink P, van der Mey AG, Sandkuijl LA, et al. 1992 A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter. Hum Mol Genet. 1:7–10.[Abstract/Free Full Text]
  17. Milunsky J, DeStefano AL, Huang XL, et al. 1997 Familial paragangliomas: linkage to chromosome 11q23 and clinical implications. Am J Med Genet. 72:66–70.[CrossRef][Medline]
  18. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. 2000 Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 287:848–851.[Abstract/Free Full Text]
  19. Scheffler IE. 1998 Molecular genetics of succinate:quinone oxidoreductase in eukaryotes. Prog Nucleic Acids Res Mol Biol. 60:267–315.[Medline]
  20. Ackrell BA. 2000 Progress in understanding structure-function relationships in respiratory chain complex II. FEBS Lett. 466:1–5.[CrossRef][Medline]
  21. Maxwell PH, Wiesener MS, Chang GW, et al. 1999 The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 399:271–275.[CrossRef][Medline]
  22. Dahia PL, Aguiar RC, Tsanaclis AM, et al. 1995 Molecular and immunohistochemical analysis of P53 in phaeochromocytoma. Br J Cancer. 72:1211–1213.[Medline]
  23. Dahia PLM, Aguiar RCT, Alberta J, et al. 1999 PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum Mol Genet. 8:185–193.[Abstract/Free Full Text]
  24. Dahia PL, Marsh DJ, Zheng Z, et al. 1997 Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 57:4710–4713.[Abstract/Free Full Text]
  25. Aguiar RC, Yakushijin Y, Kharbanda S, Salgia R, Fletcher J, Shipp MA. 2000 BAL is a novel risk-related gene in diffuse large B-cell lymphomas which enhances cellular migration. Blood. 96:4328–4334.[Abstract/Free Full Text]
  26. Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K. 1997 Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23. Cytogenet Cell Genet. 79:132–138.[Medline]
  27. Vanin EF. 1985 Processed pseudogenes: characteristics and evolution. Annu Rev Genet. 19:253–272.[CrossRef][Medline]
  28. Maestre J, Tchenio T, Dhellin O, Heidmann T. 1995 mRNA retroposition in human cells: processed pseudogene formation. EMBO J. 14:6333–6338.[Medline]
  29. Gilbert W, Souza SJ, Long M. 1997 Origin of genes. Proc Natl Acad Sci USA. 94:7698–7703.[Abstract/Free Full Text]
  30. Dahia PL, FitzGerald MG, Zhang X, et al. 1998 A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene. 16:2403–2406.[CrossRef][Medline]
  31. Hirawake H, Taniwaki M, Tamura A, Amino H, Tomitsuka E, Kita K. 1999 Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate-ubiquinone oxidoreductase. Biochim Biophys Acta. 1412:295–300.[Medline]
  32. Semenza GL. 2000 HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 88:1474–1480.[Abstract/Free Full Text]
  33. Wenger RH. 2000 Mammalian oxygen sensing, signalling and gene regulation. J Exp Biol 203:1253–1263.
  34. Richard DE, Berra E, Pouyssegur J. 1999 Angiogenesis: how a tumor adapts to hypoxia. Biochem Biophys Res Commun. 266:718–722.[CrossRef][Medline]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals