BIX 02188 FOR STEADY FLOW

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BIX 02188 FOR STEADY FLOW

Posted On : Jan-09-2012 | seen (1983) times | Article Word Count : 890 |

INTRODUCTION

A steady blood flow is the only case of prevention of atherosclerosis. A shear stress can cause the prevention of hardening of blood vessels. So when a shear stress is exerted by flow of fluid, it results in the in vivo prevention of atherosclerosis. Atherosclerosis leading to oxidative stress also accompanied with expression of VCAM1 increased inflammation.. A steady blood flow decreases VCAM1 expression mediated by TNF-?. BIX02188 is among MAPK inhibitors and selectively inhibits MEK5 and can oppose the actions of steady flow of blood, so it’s a kinase inhibitor [1].

BIX 02188: ROLE IN INHIBITING JNK

Blood flow by inhibiting JNK can control the VCAM1 expression mediated by TNF-?. A group of MAPK kinases activated by fluid flow inhibits the phosphorylation and cause stimulation of ASK1-JNK which is downstream. MEK5 is found to be the best target to stop the actions of flow. A constant flow blocked the apoptosis present inside the endothelial cells via MEK5-BMK1 activation pathway. PKC- activation also inhibits the apoptosis mediated by flow. Both the ERK1/2 and BMK1 are in fact activated by this flow and certain inhibitors such as BI6727 and CHIR-99021 inhibit this activation. Phosphorylation of BMK1 selectively inhibited by BIX02188 in and this process is dose dependent. MEK5-BMK1 pathway is utilized by TNF-? to activate JNK. The inhibitor BIX02188 reverses the flow induced activity of JNK completely [1].

BIX 02188 TARGETS BMK1

Cell death in endothelial cells is prevented by BMK1 or known as Big Mitogen-Activated Protein Kinase, alternatively is also called as ERK5. Short fall of growth factor causes the activation of apoptosis of the cancer cells by enhancing the activity of caspase-3 up to 5.2 times. Over expression of MEK5 is inhibited by this caspase activity. The shear stress stimulated by the CA-MEK5 or fluid, induces the activity of Bad protein, which in turn causes phosphorylation of the Bad protein at dual sites that are Ser136 and Ser112. BMK1, infect is responsible of inhibition of this phosphorylation [2]. BMK1 is inhibited by BIX 02188 as a result death of endothelial cells is promoted by this phosphorylation.

BIX 02188 AND THE STUDY OF ERK5 FUNCTION IN NEURONAL CELLS

A very helpful thing for the scientists is the discovery of MEK5/ERK5‘s selective inhibitor. It helped them to find the role of BMK1 / ERK5 in in vivo and in vitro survival of neurons and enhanced levels of differentiation. Activation pathway of ERK1/2 is more studied then ERK5 activation pathway. Amino terminus of ERK5 and ERK1/2 are 50% homologous and are neighboring proteins while almost a half of amino terminal of ERK5 is responsible for coding the kinase domain. Carboxyl terminal of ERK5 is unique and this unique carboxy terminus codes for a one gene of nuclear localization signal (NLS) and also 2 high proline regions [3] [4]. Tyrosine and threonine residues of ERK5 are phosphorylated by MEK5. A MEKK2,3/MEK5 mediated kinase cascade makes the G-Protein-Coupled Receptors (GPCR) able to stimulate ERK5 via Ras/MEK1/2/Raf or B-Raf/Rap1/MEK1/2 pathways [5].This activation causes the stimulation of cell differentiation and proliferation. Neuronal tissues development is also a key role of ERK5.

CONCLUSION

In short BIX 02188 is proved to be an efficient inhibitor of kinases and is also an active compound of MAPK inhibitors. The main targets like ERK5, MEK5 and BMK1 are strongly inhibited by BIX 02188. The inhibition of vital MAPKs leads to the cell death or apoptosis. This compound was active during various in vivo and in vitro studies proving its potential in cancer treatment and is found to be one of the active members of apoptosis inhibitors.

REFERENCES

1. Li L, Tatake RJ, et al. Fluid shear stress inhibits TNF-mediated JNK activation via MEK5-BMK1 in endothelial cells. Biochem Biophys Res Commun 2008 May 23; 370(1):159-63.

2. Pi X, Yan C, Berk BC. Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis. Circ Res 2004 Feb 20; 94(3):362-9.

3. Nishimoto S, Nishida E. MAPK signalling: ERK5 versus ERK1/2. EMBO Rep 2006 Aug; 7(8):782-6.

4. Wang X, Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal 2006 Jun; 18(6):753-60.

5. Obara Y, Nakahata N. The signaling pathway leading to extracellular signal-regulated kinase 5 (ERK5) activation via G-proteins and ERK5-dependent neurotrophic effects. Mol Pharmacol 2010 Jan; 77(1):10-6.

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<h1>BIX 02188 FOR STEADY FLOW</h1> Author: <a href='http://www.articleseen.com/profile_Dr.Rabia.aspx'>Dr.Rabia</a> INTRODUCTION

A steady blood flow is the only case of prevention of atherosclerosis. A shear stress can cause the prevention of hardening of blood vessels. So when a shear stress is exerted by flow of fluid, it results in the in vivo prevention of atherosclerosis. Atherosclerosis leading to oxidative stress also accompanied with expression of VCAM1 increased inflammation.. A steady blood flow decreases VCAM1 expression mediated by TNF-?. BIX02188 is among MAPK inhibitors and selectively inhibits MEK5 and can oppose the actions of steady flow of blood, so it’s a kinase inhibitor [1].

BIX 02188: ROLE IN INHIBITING JNK

Blood flow by inhibiting JNK can control the VCAM1 expression mediated by TNF-?. A group of MAPK kinases activated by fluid flow inhibits the phosphorylation and cause stimulation of ASK1-JNK which is downstream. MEK5 is found to be the best target to stop the actions of flow. A constant flow blocked the apoptosis present inside the endothelial cells via MEK5-BMK1 activation pathway. PKC- activation also inhibits the apoptosis mediated by flow. Both the ERK1/2 and BMK1 are in fact activated by this flow and certain inhibitors such as BI6727 and CHIR-99021 inhibit this activation. Phosphorylation of BMK1 selectively inhibited by BIX02188 in and this process is dose dependent. MEK5-BMK1 pathway is utilized by TNF-? to activate JNK. The inhibitor BIX02188 reverses the flow induced activity of JNK completely [1].

BIX 02188 TARGETS BMK1

Cell death in endothelial cells is prevented by BMK1 or known as Big Mitogen-Activated Protein Kinase, alternatively is also called as ERK5. Short fall of growth factor causes the activation of apoptosis of the cancer cells by enhancing the activity of caspase-3 up to 5.2 times. Over expression of MEK5 is inhibited by this caspase activity. The shear stress stimulated by the CA-MEK5 or fluid, induces the activity of Bad protein, which in turn causes phosphorylation of the Bad protein at dual sites that are Ser136 and Ser112. BMK1, infect is responsible of inhibition of this phosphorylation [2]. BMK1 is inhibited by BIX 02188 as a result death of endothelial cells is promoted by this phosphorylation.

BIX 02188 AND THE STUDY OF ERK5 FUNCTION IN NEURONAL CELLS

A very helpful thing for the scientists is the discovery of MEK5/ERK5‘s selective inhibitor. It helped them to find the role of BMK1 / ERK5 in in vivo and in vitro survival of neurons and enhanced levels of differentiation. Activation pathway of ERK1/2 is more studied then ERK5 activation pathway. Amino terminus of ERK5 and ERK1/2 are 50% homologous and are neighboring proteins while almost a half of amino terminal of ERK5 is responsible for coding the kinase domain. Carboxyl terminal of ERK5 is unique and this unique carboxy terminus codes for a one gene of nuclear localization signal (NLS) and also 2 high proline regions [3] [4]. Tyrosine and threonine residues of ERK5 are phosphorylated by MEK5. A MEKK2,3/MEK5 mediated kinase cascade makes the G-Protein-Coupled Receptors (GPCR) able to stimulate ERK5 via Ras/MEK1/2/Raf or B-Raf/Rap1/MEK1/2 pathways [5].This activation causes the stimulation of cell differentiation and proliferation. Neuronal tissues development is also a key role of ERK5.

CONCLUSION

In short BIX 02188 is proved to be an efficient inhibitor of kinases and is also an active compound of MAPK inhibitors. The main targets like ERK5, MEK5 and BMK1 are strongly inhibited by BIX 02188. The inhibition of vital MAPKs leads to the cell death or apoptosis. This compound was active during various in vivo and in vitro studies proving its potential in cancer treatment and is found to be one of the active members of apoptosis inhibitors.

REFERENCES

1. Li L, Tatake RJ, et al. Fluid shear stress inhibits TNF-mediated JNK activation via MEK5-BMK1 in endothelial cells. Biochem Biophys Res Commun 2008 May 23; 370(1):159-63.

2. Pi X, Yan C, Berk BC. Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis. Circ Res 2004 Feb 20; 94(3):362-9.

3. Nishimoto S, Nishida E. MAPK signalling: ERK5 versus ERK1/2. EMBO Rep 2006 Aug; 7(8):782-6.

4. Wang X, Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal 2006 Jun; 18(6):753-60.

5. Obara Y, Nakahata N. The signaling pathway leading to extracellular signal-regulated kinase 5 (ERK5) activation via G-proteins and ERK5-dependent neurotrophic effects. Mol Pharmacol 2010 Jan; 77(1):10-6.

Related Posts:
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Related to BIX 02188: A STRONG INHIBITOR OF STEADY FLOW

BIX02188: HELPS IN THE STUDY OF PHYSIOLOGICAL ROLE OF ERK5

INTRODUCTION During atherosclerosis, the walls of the arteries get thickened and hardened due to the deposition of fats towards the inner side of the walls. ...
    BIX 02189 – HELPS IN THE STUDY OF MEK5/ERK5 PATHWAY

INTRODUCTION ERK5 is a member of the MAPK family of proteins. Its activation is required the regular maintenance and growth of neuronal tissues. BIX 02189 ...
    SB590885 – AN EFFICIENT INHIBITOR TO MUTATED B-RAF

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As one of the world leading suppliers of high-performance life-science products. We have over 8,000 products which consist of inhibitors, antibodies, RNAis, proteins and peptides those which focus on signaling pathways such as AZD6244, Selumetinib, xl880 & so on. Furthermore, compound libra

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