Sonic Hedgehog Stimulates Mouse Embryonic Stem Cell Proliferation by Cooperation of Ca2+/Protein Kinase C and Epidermal Growth Factor Receptor As Well as Gli1 Activation

Heo, Jung Sun; Lee, Min Young; Han, Ho Jae

doi:10.1634/stemcells.2007-0550

Cited by 72 publications

(61 citation statements)

References 56 publications

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“…Furthermore, here, we show that another selective Notch inhibitor, L-685,458, is equally ineffective in impairing both GBM TIC viability and Notch1 processing, even when used at concentrations higher than the ones previously reported as effective (42)(43)(44)(45). Interestingly, the potency in growth suppression of DAPT was reported as mild compared with LLNle also in a different cellular system (46).…”

Section: Discussionmentioning

confidence: 59%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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Section: Discussionmentioning

confidence: 59%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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“…The universal character of second-messenger signaling predicts that this pathway is common to different cell types, although different classes of cells may exhibit distinctive second-messenger dynamics (51,52). It will be of interest to investigate how these steps of decoding Shh signaling are connected to other elements of its canonical pathway and to determine the mechanisms by which the interactions between Shh, IP3, and Ca 2+ are interpreted and translated into expression of specific genes.…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord

Belgacem

Borodinsky

2011

Proc. Natl. Acad. Sci. U.S.A.

138

199

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Evolutionarily conserved hedgehog proteins orchestrate the patterning of embryonic tissues, and dysfunctions in their signaling can lead to tumorigenesis. In vertebrates, Sonic hedgehog (Shh) is essential for nervous system development, but the mechanisms underlying its action remain unclear. Early electrical activity is another developmental cue important for proliferation, migration, and differentiation of neurons. Here we demonstrate the interplay between Shh signaling and Ca 2+ dynamics in the developing spinal cord. Ca 2+ imaging of embryonic spinal cells shows that Shh acutely increases Ca 2+ spike activity through activation of the Shh coreceptor Smoothened (Smo) in neurons. Smo recruits a heterotrimeric GTP-binding protein-dependent pathway and engages both intracellular Ca 2+ stores and Ca 2+ influx. The dynamics of this signaling are manifested in synchronous Ca 2+ spikes and inositol triphosphate transients apparent at the neuronal primary cilium. Interaction of Shh and electrical activity modulates neurotransmitter phenotype expression in spinal neurons. These results indicate that electrical activity and second-messenger signaling mediate Shh action in embryonic spinal neurons.

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“…More specifically, the activation of the EGFR pathway resulted in the stimulation of transcription factors such as activator protein 1 family member JUN that cooperated with GLI1 and/or GLI2 activators for triggering selective expression of target gene products involved in the oncogenic transformation of BCC cell lines (Schnidar et al, 2009). Likewise, the stimulation of the Hh pathway can also modulate the expression and activities of EGFR signaling elements (Bigelow et al, 2005;Mimeault et al, 2006;Pasca di Magliano et al, 2006;Heo et al, 2007). For instance, it has been observed that the constitutive SHH expression was associated with an enhanced phosphorylation of EGFR in mouse embryonic stem cells and human HaCaT keratinocytes as well as an increase of collagen matrix invasion of HaCaT keratinocytes (Bigelow et al, 2005;Heo et al, 2007).…”

Section: B Cross-talks Between the Hedgehog And Epidermal Growth Facmentioning

confidence: 99%

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

2010

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Sonic Hedgehog Stimulates Mouse Embryonic Stem Cell Proliferation by Cooperation of Ca2+/Protein Kinase C and Epidermal Growth Factor Receptor As Well as Gli1 Activation

Abstract: ABSTRACT

Cited by 72 publications

References 56 publications

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

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