Interactions between HIF-1 and Jab1: Balancing Apoptosis and Adaptation

Outline of a working hypothesis
  • Mona Larsen
  • Anja Høg
  • Eva L. Lund
  • Paul E. G. Kristjansen
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 566)


When cells experience hypoxia, they either die by apoptosis or adapt to the hypoxic conditions by a series of compensatory mechanisms. Hypoxia inducible factor-1 (HIF-1) is a transcription factor involved in both processes, but the exact mechanisms regulating whether the cells survive (adapt) or perish by apoptosis are largely unknown.

We hypothesize that the balancing between apoptosis and adaptation is governed by a triangular feedback system involving the α-subunit of HIF-1, p53, and jun activating binding protein 1 (Jab1). Jab1 and p53 bind competitively to the same domain on HIF-1α resulting in either stabilization or degradation of HIF-1α, respectively. Moreover, p53 is stabilized by binding to HIF-1α, whereas its interaction with Jab1 targets p53 for degradation. Thus as a consequence we propose that the ratio between p53 and Jab1 determine whether a hypoxic induction of HIF-1 results in apoptosis or adaptation, with Jab1 as the factor promoting adaptation. On this background we consider Jab1 an interesting molecular target for anticancer therapy.


Hypoxic Induction COP9 Signalosome Hypoxic Adaptation Nuclear Export Signal Sequence Jab1 Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Ivan, and W. G. Kaelin, Jr., The von Hippel-Lindau tumor suppressor protein, Curr. Opin. Genet. Dev. 11, 27–34 (2001).PubMedCrossRefGoogle Scholar
  2. 2.
    K. Kondo and W. G. Kaelin, Jr., The von Hippel-Lindau tumor suppressor gene, Exp. Cell Res. 264, 117–125 (2001).PubMedCrossRefGoogle Scholar
  3. 3.
    J. M. Brown, Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies, Mol. Med. Today 6, 157–162 (2000).PubMedCrossRefGoogle Scholar
  4. 4.
    G. L. Semenza, HIF-1 and mechanisms of hypoxia sensing, Curr. Opin. Cell Biol. 13, 167–171 (2001).PubMedCrossRefGoogle Scholar
  5. 5.
    G. L. Semenza, Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease, Pediatr. Res. 49, 614–617 (2001).PubMedGoogle Scholar
  6. 6.
    G. L. Semenza, HIF-1: mediator of physiological and pathophysiological responses to hypoxia, J. Appl. Physiol 88, 1474–1480 (2000).PubMedGoogle Scholar
  7. 7.
    P. Carmeliet, Y. Dor, J. M. Herbert, D. Fukumura, K. Brusselmans, M. Dewerchin, M. Neeman, F. Bono, R. Abramovitch, P. Maxwell, C. J. Koch, P. Ratcliffe, L. Moons, R. K. Jain, D. Collen, E. Keshert, and E. Keshet, Role of HIF-1 alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis, Nature 394, 485–490 (1998).PubMedCrossRefGoogle Scholar
  8. 8.
    R. K. Bruick, Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia, Proc. Natl. Acad. Sci. USA 97, 9082–9087 (2000).PubMedCrossRefGoogle Scholar
  9. 9.
    W. G. An, M. Kanekal, M. C. Simon, E. Maltepe, M. V. Blagosklonny, and L. M. Neckers, Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha, Nature 392, 405–408 (1998).PubMedCrossRefGoogle Scholar
  10. 10.
    H. Suzuki, A. Tomida, and T. Tsuruo, Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia, Oncogene 20, 5779–5788 (2001).PubMedCrossRefGoogle Scholar
  11. 11.
    D. Chen, M. Li, J. Luo, and W. Gu, Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function, J. Biol. Chem. 278, 13595–13598 (2003).PubMedCrossRefGoogle Scholar
  12. 12.
    S. Salceda, I. Beck, V. Srinivas, and J. Caro, Complex role of protein phosphorylation in gene activation by hypoxia, Kidney Int. 51, 556–559 (1997).PubMedGoogle Scholar
  13. 13.
    P. Jaakkola, D. R. Mole, Y. M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, and P. J. Ratcliffe, Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation, Science 292, 468–472 (2001).PubMedGoogle Scholar
  14. 14.
    E. Minet, T. Arnould, G. Michel, I. Roland, D. Mottet, M. Raes, J. Remacle, and C. Michiels, ERK activation upon hypoxia: involvement in HIF-1 activation, FEBS Lett. 468, 53–58 (2000).PubMedCrossRefGoogle Scholar
  15. 15.
    D. E. Richard, E. Berra, E. Gothie, D. Roux, and J. Pouyssegur, p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1 alpha) and enhance the transcriptional activity of HIF-1, J. Biol. Chem. 274, 32631–32637 (1999).PubMedCrossRefGoogle Scholar
  16. 16.
    D. Lando, D. J. Peet, D. A. Whelan, J. J. Gorman, and M. L. Whitelaw, Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch, Science 295, 858–861 (2002).PubMedCrossRefGoogle Scholar
  17. 17.
    M. K. Bae, M. Y. Ahn, J. W. Jeong, M. H. Bae, Y. M. Lee, S. K. Bae, J. W. Park, K. R. Kim, and K. W. Kim, Jab1 interacts directly with HIF-1alpha and regulates its stability, J. Biol. Chem. 277, 9–12 (2002).PubMedCrossRefGoogle Scholar
  18. 18.
    R. Ravi, B. Mookerjee, Z. M. Bhujwalla, C. H. Sutter, D. Artemov, Q. Zeng, L. E. Dillehay, A. Madan, G. L. Semenza, and A. Bedi, Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha, Genes Dev. 14, 34–44 (2000).PubMedGoogle Scholar
  19. 19.
    M. V. Blagosklonny, W. G. An, L. Y. Romanova, J. Trepel, T. Fojo, and L. Neckers, p53 inhibits hypoxia-inducible factor-stimulated transcription, J. Biol. Chem. 273, 11995–11998 (1998).PubMedCrossRefGoogle Scholar
  20. 20.
    L. O. Hansson, A. Friedler, S. Freund, S. Rudiger, and A. R. Fersht, Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53, Proc. Natl. Acad. Sci. USA 99, 10305–10309 (2002).PubMedCrossRefGoogle Scholar
  21. 21.
    F. X. Claret, M. Hibi, S. Dhut, T. Toda, and M. Karin, A new group of conserved coactivators that increase the specificity of AP-1 transcription factors, Nature 383, 453–457 (1996).PubMedCrossRefGoogle Scholar
  22. 22.
    S. F. Kwok, R. Solano, T. Tsuge, D. A. Chamovitz, J. R. Ecker, M. Matsui, and X. W. Deng, Arabidopsis homologs of a c-Jun coactivator are present both in monomeric form and in the COP9 complex, and their abundance is differentially affected by the pleiotropic cop/det/fus mutations, Plant Cell 10, 1779–1790 (1998).PubMedCrossRefGoogle Scholar
  23. 23.
    M. H. Glickman, D. M. Rubin, O. Coux, I. Wefes, G. Pfeifer, Z. Cjeka, W. Baumeister, V. A. Fried, and D. Finley, A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3, Cell 94, 615–623 (1998).PubMedCrossRefGoogle Scholar
  24. 24.
    D. Bech-Otschir, R. Kraft, X. Huang, P. Henklein, B. Kapelari, C. Pollmann, and W. Dubiel, COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system, EMBO J. 20, 1630–1639 (2001).PubMedCrossRefGoogle Scholar
  25. 25.
    M. Seeger, R. Kraft, K. Ferrell, D. Bech-Otschir, R. Dumdey, R. Schade, C. Gordon, M. Naumann, and W. Dubiel, A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits, FASEB J. 12, 469–478 (1998).PubMedGoogle Scholar
  26. 26.
    K. Tomoda, Y. Kubota, and J. Kato, Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1, Nature 398, 160–165 (1999).PubMedCrossRefGoogle Scholar
  27. 27.
    K. Tomoda, Y. Kubota, Y. Arata, S. Mori, M. Maeda, T. Tanaka, M. Yoshida, N. Yoneda-Kato, and J. Y. Kato, The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex, J. Biol. Chem. 277, 2302–2310 (2002).PubMedCrossRefGoogle Scholar
  28. 28.
    L. B. Gardner, Q. Li, M. S. Park, W. M. Flanagan, G. L. Semenza, and C. V. Dang, Hypoxia inhibits G1/S transition through regulation of p27 expression, J. Biol. Chem. 276, 7919–7926 (2001).PubMedCrossRefGoogle Scholar
  29. 29.
    N. Goda, H. E. Ryan, B. Khadivi, W. McNulty, R. C. Rickert, and R. S. Johnson, Hypoxia-inducible factor 1 alpha is essential for cell cycle arrest during hypoxia, Mol. Cell Biol. 23, 359–369 (2003).PubMedCrossRefGoogle Scholar
  30. 30.
    R. M. Gemmill, L. T. Bemis, J. P. Lee, M. A. Sozen, A. Baron, C. Zeng, P. F. Erickson, J. E. Hooper, and H. A. Drabkin, The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway, Oncogene 21, 3507–3516 (2002).PubMedCrossRefGoogle Scholar
  31. 31.
    T. G. Graeber, J. F. Peterson, M. Tsai, K. Monica, A. J. Fornace, Jr., and A. J. Giaccia, Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status, Mol. Cell Biol. 14, 6264–6277 (1994).PubMedGoogle Scholar
  32. 32.
    T. G. Graeber, C. Osmanian, T. Jacks, D. E. Housman, C. J. Koch, S. W. Lowe, and A. J. Giaccia, Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours, Nature 379, 88–91 (1996).PubMedCrossRefGoogle Scholar
  33. 33.
    E. M. Hammond, N. C. Denko, M. J. Dorie, R. T. Abraham, and A. J. Giaccia, Hypoxia links ATR and p53 through replication arrest, Mol. Cell Biol. 22, 1834–1843 (2002).PubMedCrossRefGoogle Scholar
  34. 34.
    E. M. Hammond, M. J. Dorie, and A. J. Giaccia, ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to re-oxygenation, J. Biol. Chem. 278(14), 12207–12213 (2003).PubMedCrossRefGoogle Scholar
  35. 35.
    M. Achison and T. R. Hupp, Hypoxia attenuates the p53 response to cellular damage, Oncogene 22, 3431–3440 (2003).PubMedCrossRefGoogle Scholar
  36. 36.
    R.H. Wenger, G. Camenisch, I. Desbaillets, D. Chilov, and M. Gassmann, Up-regulation of hypoxia-inducible factor-1alpha is not sufficient for hypoxic/anoxic p53 induction, Cancer Res. 58, 5678–5680(1998).PubMedGoogle Scholar
  37. 37.
    K. L. Talks, H. Turley, K. C. Gatter, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe, and A. L. Harris, The expression and distribution of the hypoxia-inducible factors HIF-1 alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages, Am. J. Pathol. 157, 411–421 (2000).PubMedGoogle Scholar
  38. 38.
    K. L. Sondergaard, D. A. Hilton, M. Penney, M. Ollerenshaw, and A. G. Demaine, Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastoma, Neuropathol. Appl. Neurobiol. 28, 210–217 (2002).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Zhong, A. M. De Marzo, E. Laughner, M. Lim, D. A. Hilton, D. Zagzag, P. Buechler, W. B. Isaacs, G. L. Semenza, and J. W. Simons, Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases, Cancer Res. 59, 5830–5835 (1999).PubMedGoogle Scholar
  40. 40.
    G. L. Semenza, Hypoxia, clonal selection, and the role of HIF-1 in tumor progression, Crit Rev. Biochem. Mol. Biol. 35, 71–103 (2000).PubMedCrossRefGoogle Scholar
  41. 41.
    P. Birner, M. Schindl, A. Obermair, C. Plank, G. Breitenecker, and G. Oberhuber, Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer, Cancer Res. 60, 4693–4696 (2000).PubMedGoogle Scholar
  42. 42.
    D. M. Aebersold, P. Burri, K. T. Beer, J. Laissue, V. Djonov, R. H. Greiner, and G. L. Semenza, Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer, Cancer Res. 61, 2911–2916 (2001).PubMedGoogle Scholar
  43. 43.
    M. I. Koukourakis, A. Giatromanolaki, E. Sivridis, C. Simopoulos, H. Turley, K. Talks, K. C. Gatter, and A. L. Harris, Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer, Int. J. Radiat. Oncol. Biol. Phys. 53, 1192–1202 (2002).PubMedCrossRefGoogle Scholar
  44. 44.
    A. Unruh, A. Ressel, H. G. Mohamed, R. S. Johnson, R. Nadrowitz, E. Richter, D. M. Katschinski, and R. H. Wenger, The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy, Oncogene 12, 3213–3220 (2003).CrossRefGoogle Scholar
  45. 45.
    P. Birner, B. Gatterbauer, G. Oberhuber, M. Schindl, K. Rossler, A. Prodinger, H. Budka, and J. A. Hainfellner, Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis, Cancer 92, 165–171 (2001).PubMedCrossRefGoogle Scholar
  46. 46.
    L. Sui, Y. Dong, M. Ohno, Y. Watanabe, K. Sugimoto, Y. Tai, and M. Tokuda, Jab1 expression is associated with inverse expression of p27(kip1) and poor prognosis in epithelial ovarian tumors, Clin. Cancer Res. 7, 4130–4135 (2001).PubMedGoogle Scholar
  47. 47.
    M.A. Kouvaraki, G. Z. Rassidakis, L. Tian, R. Kumar, C. Kittas, and F. X. Claret, Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1), Cancer Res. 63, 2977–2981 (2003).PubMedGoogle Scholar
  48. 48.
    A. J. Levine, p53, the cellular gatekeeper for growth and division, Cell 88, 323–331 (1997).PubMedCrossRefGoogle Scholar
  49. 49.
    J. L. Yu, J. W. Rak, B. L. Coomber, D. J. Hicklin, and R. S. Kerbel, Effect of p53 status on tumor response to antiangiogenic therapy, Science 295, 1526–1528 (2002).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Mona Larsen
  • Anja Høg
  • Eva L. Lund
  • Paul E. G. Kristjansen

There are no affiliations available

Personalised recommendations