Skip to main content
SpringerLink
Log in

HIF-1 mediates the Warburg effect in clear cell renal carcinoma

  • Mini Review
  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. O2-dependent hydroxylation of two proline residues in the HIF-1α subunit is necessary for the binding of the von Hippel–Lindau (VHL) protein, which is a component of a ubiquitin protein ligase that ubiquitinates HIF-1α, leading to its degradation by the proteasome. In the majority of cases of the clear cell type of renal carcinoma, both VHL genes are inactivated by mutation or epigenetic silencing, leading to dysregulated HIF-1 transcriptional activity. VHL loss-of-function leads, under aerobic conditions, to a HIF-1-dependent reprogramming of glucose and energy metabolism that includes increased glucose uptake, glycolysis, and lactate production accompanied by a reciprocal decrease in respiration. These findings delineate for the first time the molecular mechanisms underlying the Warburg effect in a human cancer.

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

Similar content being viewed by others

References

  • Bruick RK, McKnight SL (2001) Science 294:1337–1340

    Article  CAS  Google Scholar 

  • Carroll RC, Ash JF, Vogt PK, Singer SJ (1978) Proc Natl Acad Sci USA 75:5015–5019

    Article  CAS  Google Scholar 

  • Craven RA, Hanrahan S, Totty N, Harnden P, Stanley AJ, Maher ER, Harris AL, Trimble WS, Selby PJ, Banks RE (2006) Proteomics 6:3880–3893

    Article  CAS  Google Scholar 

  • Ebert BL, Firth JD, Ratcliffe PJ (1995) J Biol Chem 270:29083–29089

    Article  CAS  Google Scholar 

  • Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM (2006) J Biol Chem 281:15215–15226

    Article  CAS  Google Scholar 

  • Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) Cell 107:43–54

    Article  CAS  Google Scholar 

  • Firth JD, Ebert BL, Ratcliffe PJ (1995) J Biol Chem 270:21021–21027

    Article  CAS  Google Scholar 

  • Gatenby RA, Gillies RJ (2004) Nat Rev, Cancer 4:891–899

    Article  CAS  Google Scholar 

  • Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Cell Metab 1:401–408

    Article  CAS  Google Scholar 

  • Hervouet E, Demont J, Pecina P, Vojtiskova A, Houstek J, Simonnet H, Godinot C (2005) Carcinogenesis 26:531–539

    Article  CAS  Google Scholar 

  • Hervouet E, Godinot C (2006) Mitochondrion 6:105–117

    Article  CAS  Google Scholar 

  • Hirota K, Semenza GL (2006) Crit Rev Oncol Hematol 59:15–26

    Article  Google Scholar 

  • Huang LE, Gu J, Schau M, Bunn HF (1998) Proc Natl Acad Sci USA 95:7987–7992

    Article  CAS  Google Scholar 

  • Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr (2002) Proc Natl Acad Sci USA 99:13459–13464

    Article  CAS  Google Scholar 

  • Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) Science 292:464–468

    CAS  Google Scholar 

  • Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Genes Dev 12:149–162

    CAS  Google Scholar 

  • Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim AV, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Science 292:468–472

    CAS  Google Scholar 

  • Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M (2001) FASEB J 15:1312–1314

    CAS  Google Scholar 

  • Jiang B-H, Semenza GL, Bauer C, Marti HH (1996) Am J Physiol 271:C1172–C1180

    CAS  Google Scholar 

  • Kallio PJ, Wilson WJ, O’Brien S, Makino Y, Poellinger L (1999) J Biol Chem 274:6519–6525

    Article  CAS  Google Scholar 

  • Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW (2000) Proc Natl Acad Sci USA 97:10430–10435

    Article  CAS  Google Scholar 

  • Kim J-W, Tchernyshyov I, Semenza GL, Dang CV (2006) Cell Metab 3:177–185

    Article  Google Scholar 

  • Lehninger AL (1982) Principles of biochemistry. Worth, New York

    Google Scholar 

  • Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL (2005) Blood 105:659–669

    Article  CAS  Google Scholar 

  • Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, Wykoff CC, Maher ER, Harris AL, Ratcliffe PJ, Maxwell PH (2002) Cancer Cell 1:459–468

    Article  CAS  Google Scholar 

  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher, ER, Ratcliffe PJ (1999) Nature 399:271–275

    Article  CAS  Google Scholar 

  • Meierhofer D, Mayr JA, Foetschl U, Berger A, Fink K, Schmeller N, Hacker GW, Hauser-Kronberger C, Kofler B, Sperl W (2004) Carcinogenesis 25:1005–1010

    Article  CAS  Google Scholar 

  • Motzer RJ, Bacik J, Mazumdar M (2004) Clin Cancer Res 10:6302S–6303S

    Article  CAS  Google Scholar 

  • Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) Cell Metab 3:187–197

    Article  CAS  Google Scholar 

  • Ryan HE, Lo J, Johnson RS (1998) EMBO J 17:3005–3015

    Article  CAS  Google Scholar 

  • Salceda S, Caro J (1997) J Biol Chem 272:22642–22647

    Article  CAS  Google Scholar 

  • Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K, Johnson RS (2001) Mol Cell Biol 21:3436–3444

    Article  CAS  Google Scholar 

  • Semenza GL (2003) Nat Rev Cancer 3:721–732

    Article  CAS  Google Scholar 

  • Semenza GL, Jiang B-H, Leung SW, Passantino R, Concordet J-P, Maire P, Giallongo A (1996) J Biol Chem 271:32529–32537

    Article  CAS  Google Scholar 

  • Semenza GL, Roth PH, Fang H-M, Wang GL (1994) J Biol Chem 269:23757–23763

    CAS  Google Scholar 

  • Semenza GL, Wang GL (1992) Mol Cell Biol 12:5447–5454

    CAS  Google Scholar 

  • Simonnet H, Alazard N, Pfeiffer K, Gallou C, Beroud C, Demont J, Bouvier R, Schagger H, Godinot C (2002) Carcinogenesis 23:759–768

    Article  CAS  Google Scholar 

  • Singh VN, Singh M, August JT, Horecker BL (1974) Proc Natl Acad Sci USA 71:4129–4132

    Article  CAS  Google Scholar 

  • Steck TL, Kaufman S, Bader JP (1968) Cancer Res 28:1611–1619

    CAS  Google Scholar 

  • Tian H, McKnight SL, Russell DW (1997) Genes Dev 11:72–82

    Article  CAS  Google Scholar 

  • Unwin RD, Craven RA, Harnden P, Hanrahan S, Totty N, Knowles M, Eardley I, Selby PJ, Banks RE (2003) Proteomics 3:1620–1632

    Article  CAS  Google Scholar 

  • Wang GL, Jiang B-H, Rue EA, Semenza GL (1995) Proc Natl Acad Sci USA 92:5510–5514

    Article  CAS  Google Scholar 

  • Wang GL, Semenza GL (1995) J Biol Chem 270:1230–1237

    Article  CAS  Google Scholar 

  • Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL, Wood SM, Gatter KC, Harris AL, Pugh CW, Ratcliffe PJ, Maxwell PH (1998) Blood 92:2260–2268

    CAS  Google Scholar 

  • Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL (1998) Am J Physiol 275:L818–L826

    CAS  Google Scholar 

  • Yu F, White SB, Zhao Q, Lee FS (2001) Proc Natl Acad Sci USA 98:9630–9635

    Article  CAS  Google Scholar 

  • Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) Cancer Cell 11:407–420

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vascular Biology Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Gregg L. Semenza

  2. Johns Hopkins Institute for Cell Engineering, Broadway Research Building, Suite 671, 733 North Broadway, Baltimore, MD, 21205, USA

    Gregg L. Semenza

Authors
  1. Gregg L. Semenza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregg L. Semenza.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Semenza, G.L. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 39, 231–234 (2007). https://doi.org/10.1007/s10863-007-9081-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-007-9081-2

Keywords

Search

Navigation