Hypoxia-inducible factor

The hypoxia-inducible factor (ていさんそゆうどういんし, British :Hypoxia Inducible Factor, HIF) is the protein which has been derived when the oxygen supply for the cell fell into a lack state and functions as a transcription factor. A drop of malnutrition and pH out of the cell, an oxygen understock (hypoxia) state by the lack of bloodstream are recognized in the lesion of cancer, but I increase the bloodstream to a lesion by forming a blood vessel network newly so that a cancer cell survives, and it is necessary to escape from a hypoxia state (the increase of the bloodstream leads to the security of the metastasis course). The transcription factor which puts a hypoxia condition bottom in order to take a function of that purpose, and is derived is HIF and lets you aggravate various kinds of genetic transcription. There are HIF-1α, HIF-2α, HIF-3α in HIF-α, but each these has HIF-1β developing in a cell constitutively and ability to be combined with a heterodimer. HIF-1α is produced by the normal oxygen intrusion, but does not function because it is disintegrated by the 26S proteasome which is a proteolytic enzyme complex.

Table of contents

HIF-1

 

Structure of HIF-1α.

In HIF-1α, the expression in the cell decreases in normal oxygen intrusion, but quantity of production of HIF-1α protein in itself does not decrease, and the function is controlled to minus number by the proteolysis through ubiquitin - proteasome system, and von Hippel phosphorus Dow gene product (pVHL) functioning as an ubiquitin ligase (the enzyme which ubiquitin of the protein takes one end of becoming it on) composite substrate recognition subunit participates in the resolution process [¹]; [²]. Hydroxylation participates in recognition of the protein by pVHL, but a proline (Pro) residue of the 402nd and the 564th catches the hydroxylation, and these amino acid residue is stored by the enzyme that HIF-1α holds PHD domain in HIF-2α by the amino group end side. However, the activity of PHD is hard to produce the resolution of proteasome-dependent HIF in the hypoxia state to depend on the oxygen density and is performed by normal oxygen intrusion flourishingly. After having shifted in a nucleus, in HIF-1α saved from the resolution, the combination with histone acetylation enzymes such as heterodimeric formation or CBP/p300 with HIF-1β is performed [³], and these complexes are connected to a reply element (5'-ACGTG-3') called the hypoxia responsiveness domain (Hypoxia Responsive Element, HRE) on DNA.

In addition, the tyrosine kinase connection model receptors which there is a growth factor on the cell membrane as an instruction course by the factors except the hypoxia of HIF-1α include the signal by being connected. Specifically, when a ligand binds to the receptor (HER2), PI3 kinase -Akt course and an MAP kinase course are activated and promote transcription of HIF-1α.

HIF-2α

HIF-2α may be called by names such as the Endothelial Per-ARNT-Sim (EPAS) protein and has HIF-1α and 48% of homogeny in the amino acid sequence. Expression is high in HIF-2α in the lungs and an epithelium cell mainly whereas HIF-1α develops in the organization of the whole body widely.

HIF-3α

HIF-3α was delayed more than HIF-2α and was discovered. I form HIF-1β and a heterodimer as I showed it as above and activate various kinds of genetic transcription by binding to HRE on DNA. In addition, IPAS is discovered as a splice variant of HIF-3α and develops in cerebellar Purkinje cell and corneal epithelium [⁴]. IPAS does not show transcription activity itself, but I inhibit a bond to DNA by interaction with HIF-1α and control a function of HIF-1 [⁴]. Furthermore, it is reported in the lungs and the heart that IPAS is derived in a hypoxia state [⁵], and possibility functioning as negative feedback mechanism is thought about in these organizations.

Function

When HIF-1α shifts in a nucleus, I am combined with HIF-1β. HIF-1β is combined with an aromatic hydrocarbon receptor (AhR), and it is known as a transportation carrier to work [⁶] and is called the AhR transportation carrier (Arnt). The Asp803 residue of HIF-1α carries molecular complex CBP/p300 with the histone acetyltransferase (HAT) activity to HRE on DNA and promotes the transcription of the purpose gene [⁷]. HIF participates in various genetic control, e.g., includes a vascularization and cell proliferation, glucose metabolism, pH adjustment or apoptosis. The erythropoietin which participated in the increase promotion of the red blood cell as the gene which caught the expression control was discovered for the first time in 1995 by HIF [⁸] followed by, as for the blood vessel wall growth factor (VEGF), a vascularization and cell proliferation were discovered as the gene which participated in control. In addition, HIF-1α controls various genes including adrenomedullin and matrix metalloprotease (MMPs), endothelin (ET) -1, nitric oxide synthetase (NOS) 2, and as a result of having analyzed it, it is reported with the gene of the Homo sapiens artery endothelium by the microarray method that the gene equal to 2% of the whole is controlled directly or indirectly by HIF-1α [⁹].

Source

• Kazutomo Imahori, Tamio Yamakawa editing "biochemistry dictionary fourth edition" Tokyo chemistry coterie 2007 ISBN 9784807906703
• Tannock IF,Hill RP,Bristow RG and Harrington L. "basic science Japanese edition third edition medical science international 2006 ISBN 4895924602 of cancer"

References

1. ^ Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD and Pause A.(1999) "Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex."Proc.Nat.Acad.Sci.U.S.A. 96,12,436-41. PMID 10535940
2. ^ Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M and Krek W.(1999) "The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity."Genes Dev. 13,1822-33. PMID 10421634
3. ^ Yamashita K, Discher DJ, Hu J, Bishopric NH and Webster KA.(2001) "Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP."J.Biol.Chem. 276 12,645-53. PMID 11278891
4. ^ ^{a b} Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A and Poellinger L.(2001) "Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression."Nature. 414,550-4. PMID 11734856
5. ^ Makino Y, Kanopka A, Wilson WJ, Tanaka H and Poellinger L.(2002) "Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxiainducible factor-3 locus."J.Biol.Chem 277,32,405-8. PMID 12119283
6. ^ Reyes H, Reisz-Porszasz S and Hankinson O.(1992) "Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor."Science. 256,1193-5. PMID 1317062
7. ^ Ke Q and Costa M.(2006) "Hypoxia-Inducible Factor-1 (HIF-1) "Mol.Pharmacol.70,1469-80. PMID 16887934
8. ^ Wang GL, Jiang BH, Rue EA and Semenza GL.(1995) "Hypoxiainducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellularO2 tension."Proc.Nat.Acad.Sci.U.S.A. 92,5510-4. PMID 7539918
9. ^ Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG and Semenza GL.(2005) "Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1."Blood. 105,659–669. PMID 15374877

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