Skip to main content
SpringerLink
Log in

Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1α and HIF-2α

  • Original article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Chuvash polycythemia, the first hereditary disease associated with dysregulated oxygen-sensing to be recognized, is characterized by a homozygous germ-line loss-of-function mutation of the VHL gene (VHL R200W) resulting in elevated hypoxia inducible factor (HIF)-1α and HIF-2α levels, increased red cell mass and propensity to thrombosis. Organ volume is determined by the size and number of cells, and the underlying molecular control mechanisms are not fully elucidated. Work from several groups has demonstrated that the proliferation of cells is regulated in opposite directions by HIF-1α and HIF-2α. HIF-1α inhibits cell proliferation by displacing MYC from the promoter of the gene encoding the cyclin-dependent kinase inhibitor, p21Cip1, thereby inducing its expression. In contrast, HIF-2α promotes MYC activity and cell proliferation. Here we report that the volumes of liver, spleen, and kidneys relative to body mass were larger in 30 individuals with Chuvash polycythemia than in 30 matched Chuvash controls. In Hif1a +/− mice, which are heterozygous for a null (knockout) allele at the locus encoding HIF-1α, hepatic HIF-2α mRNA was increased (2-fold) and the mass of the liver was increased, compared with wild-type littermates, without significant difference in cell volume. Hepatic p21 Cip1 mRNA levels were 9.5-fold lower in Hif1a +/− mice compared with wild-type littermates. These data suggest that, in addition to increased red cell mass, the sizes of liver, spleen, and kidneys are increased in Chuvash polycythemia. At least in the liver, this phenotype may result from increased HIF-2α and decreased p21Cip1 levels leading to increased hepatocyte proliferation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Polyakova LA (1974) Familial erythrocytosis among inhabitants of the Chuvash ASSR. Problemi Gematologii I perelivaniya Krovi 10:30–36

    Google Scholar 

  2. Gordeuk VR, Sergueeva AI, Miasnikova GY, Okhotin D, Voloshin Y, Choyke PL, Butman JA, Jedlickova K, Prchal JT, Polyakova LA (2004) Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood 103:3924–3932. doi:10.1182/blood-2003-07-2535, 2003-07-2535 [pii]

    Article  PubMed  CAS  Google Scholar 

  3. Perrotta S, Nobili B, Ferraro M, Migliaccio C, Borriello A, Cucciolla V, Martinelli V, Rossi F, Punzo F, Cirillo P, Parisi G, Zappia V, Rotoli B, Ragione FD (2006) Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. Blood 107:514–519. doi:2005-06-2422 [pii], 10.1182/blood-2005-06-2422

    Article  PubMed  CAS  Google Scholar 

  4. Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D, Maxwell PH, Stockton DW, Semenza GL, Prchal JT (2002) Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32:614–621. doi:10.1038/ng1019, ng1019 [pii]

    Article  PubMed  CAS  Google Scholar 

  5. Safran M, Kaelin WG Jr (2003) HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest 111:779–783. doi:10.1172/JCI18181

    PubMed  CAS  Google Scholar 

  6. Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402. doi:S1097-2765(08)00292-X [pii], 10.1016/j.molcel.2008.04.009

    Article  PubMed  CAS  Google Scholar 

  7. Semenza GL (2009) Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 24:97–106. doi:24/2/97 [pii], 10.1152/physiol.00045.2008

    CAS  Google Scholar 

  8. Boutin AT, Weidemann A, Fu Z, Mesropian L, Gradin K, Jamora C, Wiesener M, Eckardt KU, Koch CJ, Ellies LG, Haddad G, Haase VH, Simon MC, Poellinger L, Powell FL, Johnson RS (2008) Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell 133:223–234. doi:S0092-8674(08)00289-4 [pii], 10.1016/j.cell.2008.02.038

    Article  PubMed  CAS  Google Scholar 

  9. Hickey MM, Lam JC, Bezman NA, Rathmell WK, Simon MC (2007) von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117:3879–3889. doi:10.1172/JCI32614

    PubMed  CAS  Google Scholar 

  10. Bushuev VI, Miasnikova GY, Sergueeva AI, Polyakova LA, Okhotin D, Gaskin PR, Debebe Z, Nekhai S, Castro OL, Prchal JT, Gordeuk VR (2006) Endothelin-1, vascular endothelial growth factor and systolic pulmonary artery pressure in patients with Chuvash polycythemia. Haematologica 91:744–749

    PubMed  CAS  Google Scholar 

  11. Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, Maxwell PH, McMullin MF, McNamara CJ, Percy MJ, Pugh CW, Ratcliffe PJ, Talbot NP, Treacy M, Robbins PA (2006) Mutation of von Hippel–Lindau tumour suppressor and human cardiopulmonary physiology. PLoS Med 3:e290. doi:05-PLME-RA-0484R2 [pii], 10.1371/journal.pmed.0030290

    Article  PubMed  CAS  Google Scholar 

  12. Conlon I, Raff M (1999) Size control in animal development. Cell 96:235–244. doi:S0092-8674(00)80563-2 [pii]

    Article  PubMed  CAS  Google Scholar 

  13. Metcalf D (1964) Restricted growth capacity of multiple spleen grafts. Transplantation 2:387–392

    Article  PubMed  CAS  Google Scholar 

  14. Stanger BZ, Tanaka AJ, Melton DA (2007) Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445:886–891. doi:nature05537 [pii], 10.1038/nature05537

    Article  PubMed  CAS  Google Scholar 

  15. Muller-Sieburg CE, Cho RH, Sieburg HB, Kupriyanov S, Riblet R (2000) Genetic control of hematopoietic stem cell frequency in mice is mostly cell autonomous. Blood 95:2446–2448

    PubMed  CAS  Google Scholar 

  16. Robin C, Ottersbach K, Durand C, Peeters M, Vanes L, Tybulewicz V, Dzierzak E (2006) An unexpected role for IL-3 in the embryonic development of hematopoietic stem cells. Dev Cell 11:171–180. doi:S1534-5807(06)00303-0 [pii], 10.1016/j.devcel.2006.07.002

    Article  PubMed  CAS  Google Scholar 

  17. Weissman IL, Anderson DJ, Gage F (2001) Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol 17:387–403. doi:10.1146/annurev.cellbio.17.1.387, 17/1/387 [pii]

    Article  PubMed  CAS  Google Scholar 

  18. Bryant PJ, Simpson P (1984) Intrinsic and extrinsic control of growth in developing organs. Q Rev Biol 59:387–415

    Article  PubMed  CAS  Google Scholar 

  19. Colombani J, Bianchini L, Layalle S, Pondeville E, Dauphin-Villemant C, Antoniewski C, Carre C, Noselli S, Leopold P (2005) Antagonistic actions of ecdysone and insulins determine final size in Drosophila. Science 310:667–670. doi:1119432 [pii], 10.1126/science.1119432

    Article  PubMed  CAS  Google Scholar 

  20. Catrina SB, Botusan IR, Rantanen A, Catrina AI, Pyakurel P, Savu O, Axelson M, Biberfeld P, Poellinger L, Brismar K (2006) Hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha are expressed in kaposi sarcoma and modulated by insulin-like growth factor-I. Clin Cancer Res 12:4506–4514. doi:12/15/4506 [pii], 10.1158/1078-0432.CCR-05-2473

    Article  PubMed  CAS  Google Scholar 

  21. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J 17:5085–5094. doi:10.1093/emboj/17.17.5085

    Article  PubMed  CAS  Google Scholar 

  22. Gardner LB, Corn PG (2008) Hypoxic regulation of mRNA expression. Cell Cycle 7:1916–1924. doi:6203 [pii]

    PubMed  CAS  Google Scholar 

  23. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23:1949–1956. doi:10.1038/sj.emboj.7600196, 7600196 [pii]

    Article  PubMed  CAS  Google Scholar 

  24. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11:335–347. doi:S1535-6108(07)00059-1 [pii], 10.1016/j.ccr.2007.02.006

    Article  PubMed  CAS  Google Scholar 

  25. Haase VH, Glickman JN, Socolovsky M, Jaenisch R (2001) Vascular tumors in livers with targeted inactivation of the von Hippel–Lindau tumor suppressor. Proc Natl Acad Sci U S A 98:1583–1588. doi:10.1073/pnas.98.4.1583, 98/4/1583 [pii]

    Article  PubMed  CAS  Google Scholar 

  26. Kim WY, Safran M, Buckley MR, Ebert BL, Glickman J, Bosenberg M, Regan M, Kaelin WG Jr (2006) Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 25:4650–4662. doi:7601300 [pii], 10.1038/sj.emboj.7601300

    Article  PubMed  CAS  Google Scholar 

  27. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162

    Article  PubMed  CAS  Google Scholar 

  28. Yoon D, Pastore YD, Divoky V, Liu E, Mlodnicka AE, Rainey K, Ponka P, Semenza GL, Schumacher A, Prchal JT (2006) Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. J Biol Chem 281:25703–25711. doi:M602329200 [pii], 10.1074/jbc.M602329200

    Article  PubMed  CAS  Google Scholar 

  29. Selman C, Lumsden S, Bunger L, Hill WG, Speakman JR (2001) Resting metabolic rate and morphology in mice (Mus musculus) selected for high and low food intake. J Exp Biol 204:777–784

    PubMed  CAS  Google Scholar 

  30. Crawford BA, Singh J, Simpson JM, Handelsman DJ (1993) Androgen regulation of circulating insulin-like growth factor-I during puberty in male hypogonadal mice. J Endocrinol 139:57–65

    Article  PubMed  CAS  Google Scholar 

  31. Serste T, Bourgeois N (2006) Ageing and the liver. Acta Gastroenterol Belg 69:296–298

    PubMed  Google Scholar 

  32. Meier JM, Alavi A, Iruvuri S, Alzeair S, Parker R, Houseni M, Hernandez-Pampaloni M, Mong A, Torigian DA (2007) Assessment of age-related changes in abdominal organ structure and function with computed tomography and positron emission tomography. Semin Nucl Med 37:154–172. doi:S0001-2998(07)00022-0 [pii], 10.1053/j.semnuclmed.2007.02.001

    Article  PubMed  Google Scholar 

  33. Niu X, Miasnikova GY, Sergueeva AI, Polyakova LA, Okhotin DJ, Tuktanov NV, Nouraie M, Ammosova T, Nekhai S, Gordeuk VR (2008) Altered cytokine profiles in patients with Chuvash polycythemia. Am J Hematol. doi:10.1002/ajh.21327

    Google Scholar 

  34. Sergueeva AI, Miasnikova GY, Okhotin DJ, Levina AA, Debebe Z, Ammosova T, Niu X, Romanova EA, Nekhai S, DiBello PM, Jacobsen DW, Prchal JT, Gordeuk VR (2008) Elevated homocysteine, glutathione and cysteinylglycine concentrations in patients homozygous for the Chuvash polycythemia VHL mutation. Haematologica 93:279–282. doi:haematol.11851 [pii], 10.3324/haematol.11851

    Article  PubMed  CAS  Google Scholar 

  35. Jones R, Capen D, Jacobson M (2006) PDGF and microvessel wall remodeling in adult lung: imaging PDGF-Rbeta and PDGF-BB molecules in progenitor smooth muscle cells developing in pulmonary hypertension. Ultrastruct Pathol 30:267–281. doi:P64676738W8625L3 [pii], 10.1080/01913120600820336

    Article  PubMed  Google Scholar 

Download references

Acknowledgements and Disclosure Statement

This work was supported by the National Heart, Lung and Blood Institute and the Office of Research on Minority Health (UH1-HL03679-05 to V.R.G.); by the National Institute of Research Resources (Howard University General Clinical Research Center Grant No. MO1-RR10284); by the National Heart, Lung and Blood Institute (R01HL079912-01 to V.R.G., R01HL66333-01 to J.T.P. and V.R.G., R01HL50077-14 o J.T.P.); and by the Veterans Administration (merit grant to J.T.P.).We would like to thank the University of Utah Microarray Core Facility and Bioinformatics Core for their services and advice. Dr. Gordeuk has received consulting fees from Amgen and a grant from Merck. Daniel Okhotin has received a grant from Amgen.

Author contributions

Donghoon Yoon contributed to study design, conducting the study, analyzing the data and writing the manuscript. David Okhotin contributed to conducting the study, analyzing the data and writing the manuscript. Bumjun Kim contributed to study design, conducting the study, analyzing the data and writing the manuscript. Yulia Okhotina contributed to conducting the study and writing the manuscript. Daniel J. Okhotin contributed to study design, conducting the study and writing the manuscript. Galina Y. Miasnikova contributed to study design and conducting the study. Adelina I. Sergueeva contributed to study design and conducting the study. Lydia A. Polyakova contributed to study design and conducting the study. Alexei Maslow contributed to study design and conducting the study. Yonggu Lee contributed to study design, conducting the study, and analyzing the data. Gregg L. Semenza contributed to study design, analyzing the data and writing the manuscript. Josef T. Prchal contributed to study design, conducting the study, analyzing the data and writing the manuscript. Victor R. Gordeuk contributed to study design, conducting the study, analyzing the data and writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Utah, Salt Lake, UT, 84132, USA

    Donghoon Yoon, Yonggu Lee & Josef T. Prchal

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Bumjun Kim

  3. Center for Sickle Cell Disease, Howard University, Washington, DC, 20060, USA

    David V. Okhotin, Yulia Okhotina & Victor R. Gordeuk

  4. Russian Research Services, Camas, WA, 98607, USA

    Daniel J. Okhotin

  5. Chuvash Republic Clinical Hospital No. 1, Cheboksary, 428022, Russia

    Galina Y. Miasnikova & Lydia A. Polyakova

  6. Cheboksary Children’s Hospital, Cheboksary, 428022, Russia

    Adelina I. Sergueeva

  7. President Hospital, Moscow, 101000, Russia

    Alexei Maslow

  8. The Johns Hopkins University School of Medicine, Baltimore, MD, 21206, USA

    Gregg L. Semenza

  9. Center for Sickle Cell Disease, Howard University, 2041 Georgia Ave. NW, Washington, DC, 20060, USA

    Victor R. Gordeuk

Authors
  1. Donghoon Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David V. Okhotin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bumjun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yulia Okhotina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel J. Okhotin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Galina Y. Miasnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adelina I. Sergueeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lydia A. Polyakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alexei Maslow
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yonggu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gregg L. Semenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Josef T. Prchal
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Victor R. Gordeuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Victor R. Gordeuk.

Additional information

Donghoon Yoon and David Okhotin contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoon, D., Okhotin, D.V., Kim, B. et al. Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1α and HIF-2α. J Mol Med 88, 523–530 (2010). https://doi.org/10.1007/s00109-010-0599-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-010-0599-0

Keywords

Search

Navigation