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

Year 2014, , 171 - 177, 01.12.2014

Saygın Hasan Demirel Sümeyra Çetinkaya

https://doi.org/10.5505/sakaryamj.2014.15010

Cited By: 1

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

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