Hypoxia-inducible factor-1: Physiological and Pathological Response to Hypoxia of Cell

Abstract

Hypoxia-inducible factor 1 (HIF-1) which has a critical role in the homeostasis of oxygen, is a transcriptional regulator of metabolic processes such as angiogenesis, erythropoiesis, iron metabolism and glucose metabolism. It is also essential for the regulation of key physiological systems in the process of fetal and postnatal life. HIF-1 is a heterodimeric protein consists of HIF-1α (homologues HIF-2α and HIF-2α) that involved in the regulation of oxygen and HIF-1β subunits that situated in the nucleus. Stability and activity of HIF-1α subunit is provided with post-transcriptional modification such as hydroxylation, ubiquitination, acetylation and phosphorylation. In normoxia, this regulation that starting with two proline hydroxylation and lysine acetylation which are located in region HIF-1α oxygen-dependent degradation (ODD), is carried out with a tumor suppressor gene von Hippel-Lindau protein (pVHL) and E3 ligase complex by the ubiquitin-proteasome pathway. In hypoxic conditions, HIF-1α subunits that are not hydroxylation becomes stable and switches nucleus by activating with coactivators such as cAMP, protein/p300. Combining with HIF-1β subunit regulates the expression of genes in response to hypoxia. Overexpression of HIF-1 is determined in various cancer events and targeting HIF-1 is thought to be new approach in cancer treatment.

Keywords

• HIF-1, VHL, cancer, hypoxia

Hipoksiyle İndüklenen Faktör-1: Hücrenin Hipoksiye Fizyolojik ve Patolojik Cevabı

Abstract

Oksijen homeostazında kritik bir rol oynayan hipoksiyle indüklenen faktör-1 (HIF-1); anjiyogenezis, eritropoezis, demir metabolizması ve glukoz metabolizması gibi metabolik süreçlerin transkripsiyonel regülatörüdür. Ayrıca fetal ve posnatal hayat sürecinde anahtar fizyolojik sistemlerin düzenlenmesi için gereklidir. HIF-1 heterodimerik bir protein olup oksijen regülasyonunda rol alan HIF-1α (homologları HIF-2α ve HIF-3α) ve nükleusta bulunan HIF-1β alt ünitelerinden oluşmaktadır. HIF-1'in α alt ünitesinin stabilitesi ve aktivitesi hidroksilasyon, ubikütinasyon, asetilasyon ve fosforilasyon gibi transkripsiyon sonrası modifikasyonlarla sağlanmaktadır. Normokside, HIF1-α'nın oksijen-bağımlı degradasyon (ODD) bölgesinde yer alan iki prolinin hidroksilasyonu ve bir lizinin asetilasyonuyla başlayan bu regülasyon bir tümör baskılayıcı gen olan von Hippel-Lindau proteini (pVHL) ile E3 ligaz kompleksi tarafından ubikütin-proteazom yolu ile gerçekleştirilmektedir. Hipoksik koşullarda, hidroksillenemeyen HIF-1α alt ünitesi stabil hale gelir ve cAMP, protein/p300 gibi koaktivatörler ile etkinleşerek nükleusa geçer. HIF-1β alt ünitesi ile birleşerek hipoksiye cevap genlerinin ekspresyonunu regüle eder. HIF-1'in aşırı ekspresyonu çeşitli kanser olgularında saptanmış ve HIF-1'in hedeflenmesinin kanser tedavisinde yeni bir yaklaşım olabileceği düşünülmüştür.

Keywords

• HIF-1, VHL, kanser, hipoksi

References

1. Avni R, Cohen B, Neeman M. Hypoxic stres and cancer: Imaging the axis of evilin tumor metastasis. NMR Biomed 2011; 24: 569-581.
2. Bahadori B, Uitz E, Mayer A, Harauer J, Dam K, Truschnig-Wilders M, Pilger E, Renner W. Polymorphisms of the hypoxia-inducible factor 1 gene peripheral artery disease. Vascular Medicine 2010; 15(5): 371-374.
3. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl- hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J 2003; 22: 4082-4090.
4. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294: 1337-1340.
5. Brusselmans K, Bono F, Maxwell P, Dor Y, Dewerchin M, Collen D, Herbert JM, Carmeliet P. Hypoxia-inducible factor 2-α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J Biol Chem 2001; 276: 39192-39196.
6. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem 2001; 276: 9519-9525.
7. Conway EM, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth. Cardiovasc Res 2001; 49: 507-521.
8. Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends Biochem Sci 1999; 24: 68–72.

9. Domene C, Illingworth CJR. Effects of point mutations in pVHL on the binding of HIF-1α. Proteins 2012; 80: 733-746.
10. 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, Jaakola P, Barstead R, Hodgkin PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001; 107: 43-54.
11. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 1999; 59: 3915-3918.
12. Gorlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R. Thrombin activates the hypoxia- inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res 2001; 89: 47-54.
13. Harris AL. Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38-47.
14. Hes FJ, Höppener WM, Luijt RB, Lips CJM. Von Hippel-Lindau Disease. Hereditary Cancer Clinical Practice 2005; 3(4): 171-178.
15. Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, Maxwell PH, Ratcliffe PJ, Stuart DI, Jones EY. Structural basis for the recognition of hydroxyproline in HIF-1 by pVHL. Nature 2002; 417: 975-978.
16. Hsiao PC, Chen MK, Su SC, Ueng KC, Chen YC, Hsieh YH, Liu YF, Tsai HT, Yang SY. Hypoxia inducible factor-1a gene polymorphism G1790A and its interaction with tobacco and alcohol consumptions increase susceptibility to hepatocellular carcinoma. Journal of Surgical Onc 2010; 102: 163-169.
17. Hupp TR, Hayward RL, Vojtesek B. Strategies for p53 reactivation in human sarcoma. Cancer Cell 2012; 22(3): 283-5.
18. Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A 1996; 93(20): 10595-9.
19. Illingworth CJR, Loenarz C, Schofield CJ, Domene C. Chemical basis for the selectivity of the von Hippel Lindau tumor suppressor pVHL for prolyl- hydroxylated HIF-1alpha. Biochemistry 2010; 49: 6936-6944.
20. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292: 464-468.
21. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292: 468- 472.
22. Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA. Expression of ARNT, ARNT2, HIF1α , HIF2α and Ah receptor mRNAs in the developing mouse. Mech Dev 1998; 73: 117-123.
23. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW. Regulation and destabilization of HIF-1alpha by ARD1- mediated acetylation. Cell 2002; 111: 709-720.
24. Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: Involvement of HIF-1 in tumor progression. Cancer Res 1997; 57: 5328-5335.
25. Josko J, Gwozdz B, Jedrzejowska-Szypulka H, Hendryk S. Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. Med Sci Monit 2000; 6: 1047-1052.
26. Kaelin W. The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun 2005; 338(1): 627-38.
27. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF 1alpha ubiquitination by a reconstituted von Hippel- Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA. 2000; 97: 10430-10435.
28. Kanno H, Saljooque F, Yamamoto I, Hattori S, Yao M, Shuin T. Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation. Cancer Res 2000; 60: 2820-2924.
29. Ke Q, Costa M. Hypoxia-Inducible Factor-1 (HIF-1). Mol Pharmacol 2006; 70: 1469-1480.
30. Kelsey JL. Breast cancer epidemiology: Summary and future direction. Epidemiol Rev 1993; 15: 256-263.
31. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 2001; 7: 437-443.
32. Knechtel G, Szkandera J, Stotz M, Hofmann G, Langsenlehner U, Kripp P, Samonigg H, Renner W, Langner C, Dehchamani D, Gerger A. Single nucleotide polymorphisms in the Hypoxia-Inducible Factor-1 gene and colorectal cancer risk. Molecular Carcinogenesis 2010; 49: 805-809.
33. Konac E, Dogan I, Onen HI, Yurdakul AS, Ozturk C, Varol A, Ekmecki A. Genetic Variations in the Hypoxia-Inducible Factor-1α Gene and Lung Cancer. Experimental Biology and Medicine 2009; 234: 1109-1116.
34. Kondo K, Kim WY, Lechpammer M, Kaelin WG. Inhibition of HIF-2α is sufficient to suppress pVHL-defective tumor growth. PloS Biol 2003; 1:
35. Koukourakis MI, Giatromanolaki A, Polychronidis A, Simopoulos C, Gatter KC, Harris AL, Sivridis E. Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer. Cancer Sci 2006; 97 (7): 582-588.
36. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P, et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 2003; 63: 1138-1143.
37. Kuwai T, Kitadai Y, Tanaka S, Hiyama T, Hiyama T, Tanimoto K, Chayama K. Mutation of the von Hippel-Lindau (VHL) gene in human colorectal carcinoma: Association with cytoplasmic accumulation of hypoxia-inducible factor (HIF)-1. Cancer Sci 2004; 95: 149-153.
38. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH- 1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of HIF. Genes Dev 2002; 16: 1466-1471.
39. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001; 21: 3995-4004.
40. Lee J, Bae S, Jeong J, Kim S, Kim K. Hypoxia-inducible factor (HIF-1)α: its protein stability and biological functions. Exp Mol Med 2004; 36: 1-12.
41. Li J, Davidson G, Huang Y, Jiang BH, Shi X, Costa M, Huang C. Nickel compounds act through phosphatidylinositol-3-kinase/Akt-dependent, p70(S6k)-independent pathway to induce hypoxia inducible factor transactivation and Cap43 expression in mouse epidermal Cl41 cells. Cancer Res 2004; 64: 94-101.
42. Liao D, Corle C, Seagroves TN, Johnson RS. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 2007; 67(2): 563-572.
43. Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 2002; 277: 23111-23115.
44. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001; 15: 2675-2686.
45. Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia- inducible factor-3α locus. J Biol Chem 2002; 277: 32405-32408.
46. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 2005; 105: 659-669.
47. Manohar SM, Padgaonkar AA, Jalota-Badhwar A, Sonawane V, Rathos MJ, Kumar S, Joshi KS. A novel inhibitor of hypoxia-inducible factor-1a P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells. BMC Cancer 2011; 11: 338-348.
48. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 2001; 20: 5197-206.
49. Maynard MA, Ohh M. Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am J Nephrol 2004; 24: 1-13.
50. Maynard MA, Qi H, Chung J, Lee EHL, Kondo Y, Hara S, Conaway RC. Conaway JW, Ohh M. Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 Ubiquitin Ligase complex. J Biol Chem 2003; 278: 11032-11040.
51. Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP. Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling. Science 2002; 296: 1886-1889.
52. Minet E, Michel G, Mottet D, Raes M, Michiels C. Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation. Free Radic Biol Med 2001; 31: 847-855.
53. Ohh M, Park CW, Ivan M, Hoffman MA, Kim T, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the α-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2: 423-427.
54. Park S, Dadak AM, Haase V, Fontana L, Giaccia AJ, Johnson R. Hypoxia- induced gene expression occurs solely through the action of hypoxia- inducible factor 1α (HIF-1α): role of cytoplasmic trapping of HIF-2α. Mol Cell Biol 2003; 23: 4959-4971.
55. Prior SJ, Hagberg JM, Phares DA, Brown MD, Fairfull L, Ferrell RE, Roth SM. Sequence variation in hypoxia-inducible factor 1alpha (HIF1A): Association with maximal oxygen consumption. Physiol Genomics. 2003; 15(1): 20-6.
56. Putra A, Tanimoto K, Arifin M, Hiyama K. Hypoxia inducible factor-1alpha polymorphisms are associated with genetic aberrations in lung cancer. Respirology 2011; 16: 796-802.
57. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 2000; 14: 34-44.
58. Ryan HE, Lo J, Johnson RS. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J 1998; 17: 3005-3015.
59. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS. Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 2000; 60: 4010-4015.
60. Salnikow K, Blagosklonny MV, Ryan H, Johnson R, Costa M. Carcinogenic nickel induces genes involved with hypoxic stress. Cancer Res 2000; 60: 38-41.
61. Salnikow K, Donald SP, Bruick RK, Zhitkovich A, Phang JM, Kasprzak KS. Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress. J Biol Chem 2004; 279: 40337-40344.
62. Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, Cushing CR, Seagroves TN. Hypoxia-inducible factor 1a promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Research 2012; 14: 6-8.
63. Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K. Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol 2001; 21: 3436-3444.
64. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447-54.
65. Semenza GL. Involvement of hypoxia-inducible factor 1 in human cancer. Intern Med 2002; 41: 79-83.
66. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:
67. Semenza GL. Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1. Physiology 2008; 24: 97-106.
68. Semenza GL. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Seminars in Cancer Biology 2009; 19: 12-16.
69. Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Current Opinion in Genetics & Development 2010; 20: 51-56.
70. Shimomura M, Hinoi T, Kuroda S, Adachi T, Kawaguchi Y, Sasada T, Takakura Y, Egi H, Okajima M, Tashiro H, Nishizaka T, Ohdan H. Overexpression of Hypoxia Inducible Factor-1 Alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases. Ann Surg Oncol 2013; 10434: 2945-52.
71. Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA, Gutkind JS. The Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor upregulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res 2000; 60: 4873-4880.
72. Stiehl DP, Jelkmann W, Wenger RH, Hellwig-Burgel T. Normoxic induction of the hypoxia-inducible factor 1alpha by insulin and interleukin-1beta involves the phosphatidylinositol 3-kinase pathway. FEBS Lett 2002; 512: 157-162.
73. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. 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 2000; 157: 411-421.
74. Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 1997; 11: 72-82.
75. Vaupel P, Hockel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007; 9(8): 4010- 4015.
76. Vleugel MM, Greijer AE, Van Der WE, Van Diest PJ. Mutation analysis of the HIF-1α oxygen-dependent degradation domain in invasive breast cancer. Cancer Genetics and Cytogenetics 2005; 163: 168-172.
77. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 2002; 16: 1151-1162.
78. Whiteway M, Szostak JW. The ARD1 gene of yeast functions in the switch between the mitotic cell cycle and alternative developmental pathways. Cell 1985; 43: 483-492.
79. Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, Eckardt KU. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J 2003; 17: 271-273.
80. Yamada N, Horikava Y, Oda N, Lizuka K, Shihara N, Kishi S, Takeda J. Genetik variation in the Hypoxia-İnducible-1α gene is associated with type 2 diabet in Japanese. The Journal of Clinical Endocrinology & Metabolisma 2005; 90: 5841-47.
81. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000; 14: 391-396.