Regulation of the Notch target gene Hes-1 by TGFα induced Ras/MAPK signaling in human neuroblastoma cells

Stockhausen, Marie-Thérése; Sjölund, Jonas; Axelson, Håkan

doi:10.1016/j.yexcr.2005.07.011

Cited by 90 publications

(71 citation statements)

References 42 publications

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“…5E). Recent findings in human neuroblastoma cells also contend that Hes1 response is dependent on activation of ERK and AKT phosphorylation (Stockhausen et al, 2005). Consistent with our in vitro data, we found that deletion of ALK5 caused a reduction of phosphorylated ERK in vivo, linking ALK5-regulated Clara cell differentiation to the MEK/ERK pathway.…”

Section: Discussionsupporting

confidence: 92%

Signaling via Alk5 controls the ontogeny of lung Clara cells

Xing

et al. 2010

Development

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SUMMARYClara cells, together with ciliated and pulmonary neuroendocrine cells, make up the epithelium of the bronchioles along the conducting airways. Clara cells are also known as progenitor or stem cells during lung regeneration after injury. The mechanisms of Clara cell differentiation are largely unknown. Transforming growth factor beta (TGFb)is a multifunctional molecule with roles in normal development and disease pathogenesis. In this study, we deleted the TGFb type I receptor Alk5 in the embryonic lung epithelium using Gata5-Cre mice. Absence of Alk5 blocked Clara cell differentiation but had no effect on ciliated or pulmonary neuroendocrine cells. Hairy/Enhancer of Split-1, which is expressed in Clara cell putative 'progenitors' was found to be a downstream target of Alk5 in vivo and in vitro. Loss of Alk5-mediated signaling also stimulated Pten gene expression and inhibited ERK phosphorylation in vivo. Using lung epithelial cells, we show that Alk5-regulated Hes1 expression is stimulated through Pten and the MEK/ERK and PI3K/AKT pathways. Thus, the signaling pathway by which TGFb/ALK5 regulates Clara cell differentiation may entail inhibition of Pten expression, which in turn activates ERK and AKT phosphorylation.

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Section: Discussionsupporting

confidence: 92%

Signaling via Alk5 controls the ontogeny of lung Clara cells

Xing

et al. 2010

Development

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“…This result is congruent with the report that JNK regulation of Hes-1 expression in endothelial cells is also independent of Notch (Curry et al, 2006). In addition, transforming growth factor-␣ was found to regulate Hes-1 expression through Ras/MAPK signaling in neuroblastoma cells that is also independent of Notch signaling (Stockhausen et al, 2005). Moreover, some inflammatory stimuli were found to increase Notch expression but decrease Hes-1 transcription in microglial cells (Grandbarbe et al, 2007).…”

Section: Discussionsupporting

confidence: 90%

JNK1 Inhibits GluR1 Expression and GluR1-Mediated Calcium Influx through Phosphorylation and Stabilization of Hes-1

Lin

Lee²

2012

J. Neurosci.

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The GluR1 subunit of the AMPA receptor plays an important role in excitatory synaptic transmission and synaptic plasticity in the brain, but the regulation mechanism for GluR1 expression is largely unknown. Hairy and enhancer of split 1 (Hes-1) is a mammalian transcription repressor that regulates neuronal differentiation and development, but the role of Hes-1 in differentiated neurons is also less known. Here, we examined the molecular mechanism in regulation of GluR1 expression in rat cultured cortical neurons. We found that Hes-1 suppressed GluR1 promoter activity and decreased GluR1 expression through direct binding to the N-box and through preventing Mash1/E47 from binding to the E-box of GluR1 promoter. We also found that Hes-1 could be regulated by c-Jun N-terminal kinase (JNK1). JNK1 directly phosphorylates Hes-1 at Ser-263. Furthermore, JNK1 phosphorylation of Hes-1 stabilized the Hes-1 protein and enhanced the suppressing effect of Hes-1 on GluR1 expression. These effects were demonstrated both in the soma and at the synapse. Moreover, this JNK1-mediated signaling pathway was found to inhibit AMPA-evoked calcium influx in cortical neurons and this regulation mechanism is Notch independent. Here, we provided the first evidence that Hes-1 plays an important role in synaptic function in differentiated neurons. We also identified a novel JNK1-Hes-1 signaling pathway that regulates GluR1 expression involved in synaptic function in rat cortical neurons.

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“…91 In the TGFa-stimulates neuroblastoma, Hes1 upregulation follows ERK1/2 phosphorylation without NICD activation and low level of HASH-1 suppressed by Hes1 contributes to maintain neuroblastoma embryonic nondividing states and proliferative capacity. 92 …”

Section: Canonical Notch Signaling Pathwaymentioning

confidence: 99%