New Orally Bioavailable 2-aminobenzamide-type Histone Deacetyase Inhibitor Promotes Neurite Outgrowth via histone H3 Modification in PC12 cells: a Possible Therapeutic Candidate for Neuronal Diseases

Maruoka, Hiroki; Hosokawa, Ryo

doi:10.4172/2155-9538.s5-001

Cited by 2 publications

(4 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From the data regarding neurite outgrowth obtained by val and MS-275, it is suggested that the specificity is similar to that of MS-275. We also showed that the nur77 gene, which is a transcription factor gene, was up-regulated by K-350, which suggests that K-350 may be a candidate drug not only for cancer but also for neurodegenerative disorders via the promoted-expression of the nur77 gene [7].…”

Section: Induced Expression Of the Nur77 Gene By A Hdac Inhibitor K-mentioning

confidence: 70%

“…Thus, HDAC inhibitors have been shown to induce specific genes. Previously, we reported the up-regulation of the nur77 gene, followed by histone modification via the protein kinase A signaling pathway or HDAC inhibitor-mediated molecular mechanisms, which in turn extended the neurites of PC12 cells [6,7]. These results emphasized the importance of a control mechanism for neurite outgrowth because this step is involved in the molecular mechanism following cell survival via the transduction of an action potential and release of a neurotransmitter if severe cell damage does not occur [8].…”

mentioning

confidence: 65%

See 1 more Smart Citation

Histone Deacetylase Inhibitor for Neurodegenerative Diseases: A Possible Medicinal Strategy by Prevention of ER Stress-Mediated Apoptosis and Induction of Neurite Elongation

Shimoke

Tomioka²,

Okamoto³

et al. 2013

Clinic Pharmacol Biopharmaceut

View full text Add to dashboard Cite

Introductiontherapeutic strategy for neurodegenerative diseases. Neuronal Networks Transducing Centripetal or Centrifugal Stimulation via a Synaptic Connection ER Stress-mediated Apoptosis in the Neuronal NetworksApoptosis is an important process in vertebrate development. AbstractNeurite outgrowth is primarily necessary step to construct a neuronal network. If this step is collapsed, neurons are died and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, which are known to induce endoplasmic reticulum (ER) stress-mediated apoptosis, are occurred.It has been elucidating that histone deacetylase (HDAC) plays a crucial role in the silencing of gene expression by the specific mechanisms. Thus, HDAC inhibitors have been shown to induce specific genes. We reported the upregulation of the nur77 gene, followed by histone modification via the protein kinase A signaling pathway or HDAC inhibitor-mediated molecular mechanisms. Then, we also focused on neurite outgrowth as a functional neuronal marker, and then described molecular targets and progressive pharmaceutical care for neurodegenerative disorders by using K-350. We propose that this kind of the candidate compound might contribute to build the therapeutic strategy for neurodegenerative diseases.

show abstract

Section: Induced Expression Of the Nur77 Gene By A Hdac Inhibitor K-mentioning

confidence: 70%

mentioning

confidence: 65%

Histone Deacetylase Inhibitor for Neurodegenerative Diseases: A Possible Medicinal Strategy by Prevention of ER Stress-Mediated Apoptosis and Induction of Neurite Elongation

Shimoke

Tomioka²,

Okamoto³

et al. 2013

Clinic Pharmacol Biopharmaceut

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that expression of nur77 is significantly increased by db-cAMP in PC12 cells, and that Nur77 is essential for early stage of differentiation in neurons and Schwann cells 20,34,35,44 . To investigate whether the increased expression of Nur77 is mainly responsible for neurite outgrowth that occurs from 0 to 24 hr after 10 µM forskolin treatment, expression of nur77 gene and Nur77 induced by forskolin was examined using qPCR and immunoblotting analysis ( Fig.…”

Section: Resultsmentioning

confidence: 94%

“…CRE sites near the TSS are known to be heavily involved in regulation of transcription. In PC12 cells, we have shown that the CRE site-containing nur77 promoter region near the TSS is associated with acetylated Lys14 of histone H3 after treatment with db-cAMP or HDAC (Histone Deacetylase) inhibitors TSA and K350; and that expression of Nur77 induced by db-cAMP is regulated by the PKA-CREB pathway 20,34,35 . Based on these findings, it is likely that CRE sites upstream of the TSS of nur77 and CREB are important for nur77 expression.…”

Section: Binding Of Creb With Cre Sites Near the Tss Of Nur77 Is Respmentioning

confidence: 99%

Molecular mechanism of nur77 gene expression and downstream target genes in the early stage of forskolin-induced differentiation in PC12 cells

Maruoka

Yamazoe

Takahashi

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Forskolin promotes neuronal differentiation of PC12 cells via the PKA-CREB-dependent signaling pathway. Activation of PKA by forskolin phosphorylates CREB, which then binds to CRE sites in numerous gene promoters. However, it is unclear which gene contains the CRE sites responsible for forskolin-induced neuronal differentiation. In this study, we investigated how an immediate early gene, nur77, which has CRE sites in the promoter region, contributes to the early stage of differentiation of forskolin-treated PC12 cells. After treatment with forskolin, expression of Nur77 was upregulated within 1 hr. In addition, knockdown of nur77 inhibited neurite outgrowth induced by forskolin. We also revealed that the specific four CRE sites near the transcriptional start site (TSS) of nur77 were strongly associated with phosphorylated CREB within 1 hr after treatment with forskolin. To analyze the roles of these four sites, reporter assays using the nur77 promoter region were performed. the results showed that nur77 expression was mediated through three of the cRe sites, −242, −222, and −78, and that −78, the nearest of the three to the TSS of nur77, was particularly important. An analysis of neuronal markers controlled by Nur77 after A-CREB-Nur77-Synapsin1 signaling pathway plays a pivotal role in differentiation of forskolin-induced PC12 cells. Low molecular weight natural products may be useful therapeutic agents for neuronal injury 1-6 , and some of these compounds possess neurotrophic and neuroprotective properties 7. Natural products also enhance neurite outgrowth activity of nerve growth factors in experimental models 8 , but the detailed molecular mechanisms underlying the neurotrophic and neuroprotective effects of natural products have not been clearly defined. One such natural product, forskolin, is a cell-permeable diterpenoid extracted from the plant Coleus forskohlii. Forskolin also has blood-brain barrier (BBB) permeability 9. Therefore, forskolin is a potential therapeutic agent for nerve injury, and several studies have shown that forskolin increases the differentiation and survival of dopaminergic neurons in vitro 10-14. Forskolin also induces expression of tyrosine hydroxylase in human fetal brain cortex 15. In addition, forskolin increases the intracellular cAMP level by stimulation of adenylate cyclase, and cAMP-dependent signaling pathways play important roles in neuronal differentiation and neuroplasticity 16,17. Increased cAMP in cells promotes axonal regeneration and neurite outgrowth 18-20 , and it is well-known that cAMP promotes neurite outgrowth by binding to and activating protein kinase A (PKA) 21-23. Activated PKA phosphorylates cAMP response element-binding protein (CREB), which then binds to CRE (cAMP response element) sites in various gene promotor regions 24-26. Some CREB target genes have been identified as immediate early genes (IEGs) that are induced in a CRE-dependent manner. Expression of IEGs can be induced within 1 hr in response to stimuli such as neurotrophin/Trk-or cAMP/PKA-depend...

show abstract

New Orally Bioavailable 2-aminobenzamide-type Histone Deacetyase Inhibitor Promotes Neurite Outgrowth via histone H3 Modification in PC12 cells: a Possible Therapeutic Candidate for Neuronal Diseases

Cited by 2 publications

References 24 publications

Histone Deacetylase Inhibitor for Neurodegenerative Diseases: A Possible Medicinal Strategy by Prevention of ER Stress-Mediated Apoptosis and Induction of Neurite Elongation

Histone Deacetylase Inhibitor for Neurodegenerative Diseases: A Possible Medicinal Strategy by Prevention of ER Stress-Mediated Apoptosis and Induction of Neurite Elongation

Molecular mechanism of nur77 gene expression and downstream target genes in the early stage of forskolin-induced differentiation in PC12 cells

Contact Info

Product

Resources

About