Global Gene Expression Analysis of ERK5 and ERK1/2 Signaling Reveals a Role for HIF-1 in ERK5-mediated Responses

Abstract

ERK5 is a recently characterized MAPK, which is most similar to the well studied ERK1/2 subfamily but uses distinct mechanisms to elicit responses. To understand the specificity of signaling through ERK5 versus ERK1/2, we examined global gene expression changes in response to each pathway. Microarray measurements in retinal pigment epithelial cells revealed 36 genes regulated by ERK5, all which were novel targets for this pathway. 39 genes were regulated by ERK1/2, which included 11 known genes. Of these genes, 19 were regulated by both pathways. Inspection of the 17 genes uniquely regulated by ERK5 revealed that 14 genes (82%) were previously associated with hypoxia via regulation by HIF-1. In contrast, 16 genes (84%) regulated by either ERK5 or ERK1/2 were implicated in hypoxia, most through mechanisms independent of HIF-1. Of the 20 genes regulated by ERK1/2, only 9 were implicated in hypoxia and were not well characterized hypoxia targets. Thus, unlike ERK5, a mechanistic link between ERK1/2 and HIF-1/HRE could not be established on the basis of gene regulation. Activation of both pathways enhanced transcription from a hypoxiaresponse element and increased HIF-1␣ protein expression. In contrast, ERK5 but not ERK1/2 elevated transcription through GAL4-HIF-1. Most interestingly, ERK5 is not significantly activated by hypoxia in retinal pigment epithelial cells, indicating that ERK5 regulation of these genes is relevant in normoxia rather than hypoxia. Thus, ERK5 and ERK1/2 differ in their mechanisms of gene regulation, and indicate that ERK5 may control hypoxia-responsive genes by a mechanism independent of HIF-1␣ expression control.

ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells

“…In agreement with previous studies (Barros and Marshall, 2005;Schweppe et al, 2006), co-transfection of HDMECs with ERK5(wt) and CA-MEK5(D) induced an increase in ERK5 phosphorylation (Fig. 5).…”

Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis

“…Indeed, it has been reported a direct control of HIF-1alpha by several MAPK [23] and in addition ERK5 has been proposed as a putative target of the VHL signaling axis [7] known to share biological targets with HIF-1alpha [24]. Regarding ERK5 our data show prominent up-regulation in tumor samples vs. normal tissue in a high percentage of ccRCC samples, in agreement with a putative target for VHL deregulation.…”

Altered Detoxification Status and Increased Resistance to Oxidative Stress by K-Ras Transformation

“…Several other groups analyzed global gene expression changes mediated by Ras transformation or the MAPK pathway (19,20,(24)(25)(26)(27)(28)(29). The upregulation of triosephosphate isomerase, pyruvate kinase M2, esterase D, and annexin I is in line with the results of the proteome analyses of in vitro models of the H-Ras-mediated transformation of murine fibroblasts (20,26,28).…”