TY - JOUR
T1 - Induction of hypoxia-inducible factor 1 activity by muscarinic acetylcholine receptor signaling
AU - Hirota, Kiichi
AU - Fukuda, Ryo
AU - Takabuchi, Satoshi
AU - Kizaka-Kondoh, Shinae
AU - Adachi, Takehiko
AU - Fukuda, Kazuhiko
AU - Semenza, Gregg L.
PY - 2004/10/1
Y1 - 2004/10/1
N2 - Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular adaptive responses to hypoxia. Levels of the HIF-1α subunit increase under hypoxic conditions. Exposure of cells to growth factors, prostaglandin, and certain nitric oxide donors also induces HIF-1α expression under non-hypoxic conditions. We demonstrate that muscarinic acetylcholine signals induce HIF-1α expression and transcriptional activity in a receptor subtype-specific manner using HEK293 cells transiently overexpressing each of M1-M4 muscarinic acetylcholine receptors. The muscarinic signaling pathways inhibited HIF-1α hydroxylation and degradation and induced HIF-1α protein synthesis that was confirmed by pulse labeling studies. Muscarinic signal-induced HIF-1α protein and HIF-1-dependent gene expression were blocked by treating cells with inhibitors of phosphatidylinositol 3-kinase, MAP kinase kinase, or tyrosine kinase signaling pathways. Dominant-negative forms of Ras and/or Rac-1 significantly suppressed HIF-1 activation by muscarinic signaling. Signaling via M1- and M3- but not M2-or M4-AchRs promote accumulation and transcriptional activation of HIF-1α. We conclude that muscarinic acetylcholine signals activate HIF-1 by both stabilization and synthesis of HIF-1α and by inducing the transcriptional activity of HIF-1α.
AB - Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular adaptive responses to hypoxia. Levels of the HIF-1α subunit increase under hypoxic conditions. Exposure of cells to growth factors, prostaglandin, and certain nitric oxide donors also induces HIF-1α expression under non-hypoxic conditions. We demonstrate that muscarinic acetylcholine signals induce HIF-1α expression and transcriptional activity in a receptor subtype-specific manner using HEK293 cells transiently overexpressing each of M1-M4 muscarinic acetylcholine receptors. The muscarinic signaling pathways inhibited HIF-1α hydroxylation and degradation and induced HIF-1α protein synthesis that was confirmed by pulse labeling studies. Muscarinic signal-induced HIF-1α protein and HIF-1-dependent gene expression were blocked by treating cells with inhibitors of phosphatidylinositol 3-kinase, MAP kinase kinase, or tyrosine kinase signaling pathways. Dominant-negative forms of Ras and/or Rac-1 significantly suppressed HIF-1 activation by muscarinic signaling. Signaling via M1- and M3- but not M2-or M4-AchRs promote accumulation and transcriptional activation of HIF-1α. We conclude that muscarinic acetylcholine signals activate HIF-1 by both stabilization and synthesis of HIF-1α and by inducing the transcriptional activity of HIF-1α.
UR - http://www.scopus.com/inward/record.url?scp=4744365128&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4744365128&partnerID=8YFLogxK
U2 - 10.1074/jbc.M405164200
DO - 10.1074/jbc.M405164200
M3 - Article
C2 - 15280370
AN - SCOPUS:4744365128
SN - 0021-9258
VL - 279
SP - 41521
EP - 41528
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -