scholarly journals JNK inhibitors: is there a future?

MAP Kinase ◽  
2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Jonas Cicenas
Keyword(s):  
Transcriptional Activation ◽  
Neurodegenerative Disorders ◽  
Map Kinases ◽  
Therapeutic Potential ◽  
Osmotic Shock ◽  
Basic Research ◽  
Biological Processes ◽  
Transcriptional Activation Domain ◽  
Jnk Inhibitors ◽  
Response To Stress

JNK is a subfamily of MAP kinases that hat regulates a range of biological processes implicated in response to stress, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock as well as growth factors like PDGF, EGF, FGF, <em>etc</em>. They were originally identified as kinases that bind and phosphorylate JUN on S63 and Se73 within its transcriptional activation domain. The deregulation of these kinases is shown to be involved in human diseases, such as cancer, immune diseases and neurodegenerative disorders. The realization of the therapeutic potential of the inhibition of JNKs led to a thorough search for small-molecule inhibitors first for research purposes, but later also for therapeutic applications. Here, we discuss some of the most well-known JNK inhibitors and their use in basic research or clinical science.

scholarly journals Activation of a C-terminal Transcriptional Activation Domain of ERK5 by Autophosphorylation

2007 ◽  
Vol 282 (49) ◽  
pp. 35449-35456 ◽  
Author(s):  
Hiroko Morimoto ◽  
Kunio Kondoh ◽  
Satoko Nishimoto ◽  
Kazuya Terasawa ◽  
Eisuke Nishida
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Kinase Activity ◽  
Regulation Of Gene Expression ◽  
Kinase Domain ◽  
Biological Processes ◽  
Activation Domain ◽  
Transcriptional Activation Domain ◽  
Fibroblastic Cells

ERK5 plays a crucial role in many biological processes by regulating transcription. ERK5 has a large C-terminal-half that contains a transcriptional activation domain. However, it has remained unclear how its transcriptional activation activity is regulated. Here, we show that the activated kinase activity of ERK5 is required for the C-terminal-half to enhance the AP-1 activity, and that the activated ERK5 undergoes autophosphorylation on its most C-terminal region. Changing these phosphorylatable threonine and serine residues to unphosphorylatable alanines significantly reduces the transcriptional activation activity of ERK5. Moreover, phosphomimetic mutants of the C-terminal-half of ERK5 without an N-terminal kinase domain are shown to be able to enhance the AP-1 activity in fibroblastic cells. These results reveal the role of the stimulus-induced ERK5 autophosphorylation in regulation of gene expression.

Therapeutic Potential of Cannabinoids in Neurodegenerative Disorders: A Selective Review

2014 ◽  
Vol 20 (13) ◽  
pp. 2218-2230 ◽  
Author(s):  
Latha Velayudhan ◽  
Erik Diepen ◽  
Mangesh Marudkar ◽  
Oliver Hands ◽  
Srinivas Suribhatla ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Therapeutic Potential ◽  
Selective Review

scholarly journals Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

2020 ◽  
Vol 6 (46) ◽  
pp. eabc1428
Author(s):  
A. Nakano-Kobayashi ◽  
A. Fukumoto ◽  
A. Morizane ◽  
D. T. Nguyen ◽  
T. M. Le ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Neuronal Survival ◽  
Disease Model ◽  
Neuronal Loss ◽  
Induced Pluripotent Stem Cell ◽  
Related Factor ◽  
Induced Pluripotent ◽  
Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

scholarly journals Targeting of p38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors

1999 ◽  
Vol 19 (6) ◽  
pp. 4028-4038 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Alex Galanis ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Map Kinases ◽  
Biological Response ◽  
Extracellular Signals ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein (MAP) kinase-mediated signalling to the nucleus is an important event in the conversion of extracellular signals into a cellular response. However, the existence of multiple MAP kinases which phosphorylate similar phosphoacceptor motifs poses a problem in maintaining substrate specificity and hence the correct biological response. Both the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) subfamilies of MAP kinases use a second specificity determinant and require docking to their transcription factor substrates to achieve maximal substrate activation. In this study, we demonstrate that among the different MAP kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38α and p38β2. The efficiency of phosphorylation in vitro and transcriptional activation in vivo of MEF2A and MEF2C by these p38 subtypes requires the presence of a kinase docking domain (D-domain). Furthermore, the D-domain from MEF2A is sufficient to confer p38 responsiveness on different transcription factors, and reciprocal effects are observed upon the introduction of alternative D-domains into MEF2A. These results therefore contribute to our understanding of signalling to MEF2 transcription factors and demonstrate that the requirement for substrate binding by MAP kinases is an important facet of three different subclasses of MAP kinases (ERK, JNK, and p38).

scholarly journals Fos and jun cooperate in transcriptional regulation via heterologous activation domains.

1990 ◽  
Vol 10 (10) ◽  
pp. 5532-5535 ◽  
Author(s):  
C Abate ◽  
D Luk ◽  
E Gagne ◽  
R G Roeder ◽  
T Curran
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Regulation Of Gene Expression ◽  
Negative Influence ◽  
Activation Domain ◽  
Activation Domains ◽  
Transcriptional Activation Domain ◽  
Transcriptional Stimulation

The products of c-fos and c-jun (Fos and Jun) function in gene regulation by interacting with the AP-1 binding site. Here we have examined the contribution of Fos and Jun toward transcriptional activity by using Fos and Jun polypeptides purified from Escherichia coli. Fos contained a transcriptional activation domain as well as a region which exerted a negative influence on transcriptional activity in vitro. Moreover, distinct activation domains in both Fos and Jun functioned cooperatively in transcriptional stimulation. Thus, regulation of gene expression by Fos and Jun results from an integration of several functional domains in a bimolecular complex.

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