ERK activation upon hypoxia: involvement in HIF‐1 activation

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor activated by hypoxia. The HIF-1 activation transduction pathway is poorly understood. In this report, we investigated the activation of extracellular regulated kinases (ERK) in hypoxia and their involvement in HIF-1 activation. We demonstrated that in human microvascular endothelial cells-1 (HMEC-1), ERK kinases are activated during hypoxia. Using dominant negative mutants, we showed that ERK1 is needed for hypoxia-induced HIF-1 transactivation activity. Moreover, using a kinase assay and Western blot experiments, we showed that HIF-1K K is phosphorylated in hypoxia by an ERK-dependent pathway. These results evidence the role of mitogen-activated protein kinase in the transcriptional response to hypoxia.z 2000 Federation of European Biochemical Societies.

Role for casein kinase 2 in the regulation of HIF‐1 activity

“…15 However, phosphorylation also seems to play a role as it was shown that ERK1/2 MAPK are important to increase HIF-1 activity in hypoxia in some cell types. 17,18 Since HIF-1 activation by hypoxia occurs in all cell types while ERK1/ 2 is not important for this activation in all of them, other phosphorylation events may take place. In this work, we demonstrated that CK2 could be important for regulating HIF-1 activity in hypoxia.…”

“…In addition, phosphorylation events also play a role as demonstrated by several studies: the activity of the MAP kinases ERK1/2 is needed for the transcriptional activity of HIF-1 but not for the stabilization of HIF-1a. 17,18 However, the C-terminal transactivation domain (TAD-C) of HIF-1a is not directly phosphorylated by ERKs 19 but a negative charge on threonine 796, located in the C-terminal transactivation domain of HIF-1a, seems to be essential for the interaction with CBP/p300 and hence for the activity of HIF-1. 20 These results suggest that kinases other than ERK1/2 could be involved.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…Although the link between the ERK and HIF pathway was identified soon after the discovery of HIFs, the nature of their interplay has remained less clear. Stabilised HIF-1 has been shown to be phosphorylated by p42/44 MAP kinases both under hypoxic conditions and in response to receptor-mediated ERK-activating stimuli [79][80][81]. The ERK-mediated phosphorylation was found to enhance the transcriptional activity of HIF-1 in various model systems, although the exact mechanism is still to be elucidated [82,83].…”

Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1

“…Multiple signalling pathways including the Ras/Raf/ ERK1/2 cascade have been shown to play a role in regulating HIF-1 activity and upregulating VEGF expression (Minet et al, 2000;Blancher et al, 2001;Hur et al, 2001;Sodhi et al, 2001;Fukuda et al, 2002;Lee et al, 2002;Mottet et al, 2002). Constitutive activation of the Ras/Raf/ERK1/2 pathway leads to the transformation of mammalian cells, and enhanced activity of this pathway occurs in many human cancers (Garnett and Marais, 2004;Wallace et al, 2005).…”

“…ERK1/2 has been shown to phosphorylate HIF-1a in vitro (Richard et al, 1999;Sodhi et al, 2001), whereas it has also been reported that ERK1/2 indirectly enhances HIF-1 activity by phosphorylating p300/CBP and increasing its ability to bind to HIF-1a (Sang et al, 2003). Previous studies have shown that the MEK1/2 inhibitor PD98059 or expression of dominant-negative (DN) forms of Ras, Raf or ERK1/2 all block HIF-1 activity to some degree in multiple cell types (Minet et al, 2000;Sodhi et al, 2001;Lee et al, 2002;Mottet et al, 2002). However, whether selective inhibition of ERK1/2 signalling blocks HIF-1 activity or whether ERK1/2 activation itself is essential for the induction of HIF-1a and activation of HIF-1 by hypoxia and growth factors is unclear.…”