The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling.
Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors. HIF-1α plays a prominent role in hypoxic gene induction. HIF-2α target genes are more restricted but include erythropoietin (Epo), one of the most highly hypoxia-inducible genes in mammals. We previously reported that HIF-2α is acetylated during hypoxia but is rapidly deacetylated by the stress-responsive deacetylase Sirtuin 1. We now demonstrate that the lysine acetyltransferases cAMP-response element-binding protein-binding protein (CBP) and p300 are required for efficient Epo induction during hypoxia. However, despite close structural similarity, the roles of CBP and p300 differ in HIF signaling. CBP acetylates HIF-2α, is a major coactivator for HIF-2-mediated Epo induction, and is required for Sirt1 augmentation of HIF-2 signaling during hypoxia in Hep3B cells. In comparison, p300 is a major contributor for HIF-1 signaling as indicated by induction of Pgk1. Whereas CBP can bind with HIF-2α independent of the HIF-2α C-terminal activation domain via enzyme/substrate interactions, p300 only complexes with HIF-2α through the C-terminal activation domain. Maximal CBP/HIF-2 signaling requires intact CBP acetyltransferase activity in both Hep3B cells as well as in mice.
Department of Medicine, Veterans Affairs North Texas Health Care System, Dallas, TX 75216, USA.
Rui
R
Chen
Min
M
Xu
Richard T
RT
Hogg
Jiwen
J
Li
Bertis
B
Little
Robert D
RD
Gerard
Joseph A
JA
Garcia
D000107:Acetylation; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D004921:Erythropoietin; D010446:Peptide Fragments; D010735:Phosphoglycerate Kinase; D012795:Sialoglycoproteins; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C554270:EPO protein, human; C571744:bone sialoprotein (35-62), human; C494364:Crebbp protein, mouse; C528165:Pgk1 protein, mouse; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse