Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis.

Abstract:

:Red blood cells deliver O(2) from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O(2)-regulated alpha subunit and a constitutively expressed beta subunit. Hydroxylation of HIF-1alpha or HIF-2alpha by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1alpha or HIF-2alpha by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2alpha have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.

journal_name

Blood

journal_title

Blood

authors

Semenza GL

doi

10.1182/blood-2009-05-189985

subject

Has Abstract

pub_date

2009-09-03 00:00:00

pages

2015-9

issue

10

eissn

0006-4971

issn

1528-0020

pii

blood-2009-05-189985

journal_volume

114

pub_type

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