Identification of pharmacological inhibitors of the MEK5/ERK5 pathway

Tatake, Revati J.; O’Neill, Margaret M.; Kennedy, Charles A.; Wayne, A.; Jakes, Scott; Wu, Di; Kugler, Stanley; Kashem, Mohammed A.; Kaplita, Paul V.; Snow, Roger J.

doi:10.1016/j.bbrc.2008.09.087

Cited by 139 publications

(140 citation statements)

References 32 publications

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“…Interestingly, PD184352 had no effect on NGF-and PC-induced cytoprotection (data not shown), suggesting that ERK1/2 pathway did not mediate this effect. Next, we used BIX02188 or BIX02189, two recently identified specific inhibitors against MEK5, to investigate the potential involvement of ERK5 pathway (Tatake et al 2008). Both BIX02188 and BIX02189 completely blocked the protection against H 2 O 2 by NGF (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, the physiological functions of ERK5 in the CNS and peripheral nervous system (PNS) has been poorly studied, presumably due to the lack of selective pharmacological inhibitor(s), until the recently reported BIX02188 and BIX02189 compounds (Tatake et al 2008). Further, the technical challenge of delivering interfering molecules (i.e., siRNAs) efficiently into neurons has also been only more recently addressed.…”

Section: Discussionmentioning

confidence: 99%

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ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

Sun

Cunningham

et al. 2014

AGE

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Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H 2 O 2 )-induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H 2 O 2 -caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC.Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF-or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H 2 O 2 -stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

Sun

Cunningham

et al. 2014

AGE

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“…Judging from these results, we used U0126 as a selective inhibitor for ERK1/2 signaling in this study. Recently, BIX02188 and BIX 02189 were developed as selective pharmacological inhibitors of the MEK5/ERK5 pathway (36). PC12 cells were pretreated with or without BIX02188 and BIX02189 (3-30 M) for 30 min, and the cells were stimulated with NGF (100 ng/ml) for 5 min.…”

Section: Ngf But Not Camp Induces Erk5 Phosphorylation In Pc12mentioning

confidence: 99%

ERK5 Activity Is Required for Nerve Growth Factor-induced Neurite Outgrowth and Stabilization of Tyrosine Hydroxylase in PC12 Cells

Obara

Arata²,

Takehara³

et al. 2009

Journal of Biological Chemistry

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Extracellular signal-regulated kinases (ERKs) play important physiological roles in proliferation, differentiation, and gene expression. ERK5 is approximately twice the size of ERK1/2, and its amino-terminal half contains the kinase domain that shares homology with ERK1/2 and TEY activation motif, whereas the carboxyl-terminal half is unique. In this study, we examined a physiological role of ERK5 in rat pheochromocytoma cells (PC12), comparing it with ERK1/2. Nerve growth factor (NGF) induced phosphorylation of both ERK5 and ERK1/2, whereas the cAMP analog dibutyryl cAMP (Bt 2 cAMP) caused only ERK1/2 phosphorylation. U0126, at 30 M, that blocks ERK1/2 signaling selectively attenuated neurite outgrowth induced by NGF and Bt 2 cAMP, but BIX02188 and BIX02189, at 30 M, that block ERK5 signaling and an ERK5 dominant-negative mutant suppressed only NGF-induced neurite outgrowth. Next, we examined the expression of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis. Both NGF and Bt 2 cAMP increased tyrosine hydroxylase gene promoter activity in an ERK1/2-dependent manner but was ERK5-independent. However, when both ERK5 and ERK1/2 signalings were inhibited, tyrosine hydroxylase protein up-regulation by NGF and Bt 2 cAMP was abolished, because of the loss of stabilization of tyrosine hydroxylase protein by ERK5. Taking these results together, ERK5 is involved in neurite outgrowth and stabilization of tyrosine hydroxylase in PC12 cells, and ERK5, along with ERK1/2, plays essential roles in the neural differentiation process.

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“…Osmotic pump (Alzet 1007D) was from Durect Corporation (Cupertino, CA). MEK5 inhibitor BIX02188 was kindly provided by Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT) (23). STAT5 inhibitor (NЈ-((4-oxo-4H-chromen-3-yl)methylene) nicotinohydrazide) (24) was from EMD Millipore (Billerica, MA).…”

Section: Methodsmentioning

confidence: 99%

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

Wang

Pan

Wietecha

et al. 2013

Journal of Biological Chemistry

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Background: Signaling mechanisms underlying prolactin-induced adult neurogenesis are unknown. Results: Prolactin activates ERK5 in SVZ; suppression of ERK5 expression in vitro and erk5 deletion in vivo attenuates prolactininduced adult neurogenesis. Conclusion: ERK5 is an important mediator in prolactin-stimulated adult neurogenesis. Significance: Elucidation of signaling pathways underlying prolactin-induced adult neurogenesis is critical for understanding the fundamental role of adult neurogenesis in reproductive functions and behaviors.

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Identification of pharmacological inhibitors of the MEK5/ERK5 pathway

Cited by 139 publications

References 32 publications

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

ERK5 Activity Is Required for Nerve Growth Factor-induced Neurite Outgrowth and Stabilization of Tyrosine Hydroxylase in PC12 Cells

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

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