Difference between revisions of "2009 Group 4 Project"

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===Dynamic Process===
 
===Dynamic Process===
  
[[Image: ZTrk copy.jpg|thumb|300px| '''Figure 3''': Overview of dynamic processes shared by Trk receptors. Multiple transduction pathways are employed to illicit specific responses regulating survival and differentiation. The end point of signal transduction is often gene regulation and may involve Calcium second messenger events to preciptate expressor/repressor protein dissociation/association from promoter regions.]] [[#Glossary|NGF]] binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal transductive unit- activating the kinase unit<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref>. [[#Glossary|Phosphorylation]] of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. [[#Glossary|Phosphorylation]] of an additional five tyrosines within this region promotes signalling by providing docking sites for adaptor proteins which regulate signalling-cascade couples. Overall, the purpose of this process appears to be to facilitate down-stream [[#Glossary|phosphorylation]] and gene expression regulation(Eg. upregulation of Neuronal Factor Kappa B) via multiple transductive pathways, many of which, are synonymous with tyrosine kinase receptor activity.<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref> Thus, the [[#Glossary|autophosphorylation]] of intracellular domain tyrosine residues precipitates the association of second-messenger adaptor proteins which may or may not themselves be phosphorylated in order to illicit the desired signalling event.(see dynamics overview image for some examples in addition to those below)
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[[Image: ZTrk copy.jpg|thumb|300px| '''Figure 3''': Overview of dynamic processes shared by Trk receptors. Multiple transduction pathways are employed to illicit specific responses regulating survival and differentiation. The end point of signal transduction is often gene regulation and may involve Calcium second messenger events to preciptate expressor/repressor protein dissociation/association from promoter regions.]] [[#Glossary|NGF]] binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal transductive unit- activating the kinase unit<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref>. [[#Glossary|Phosphorylation]] of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. [[#Glossary|Phosphorylation]] of an additional five tyrosines within this region promotes signalling by providing docking sites for adaptor proteins which regulate signalling-cascade couples. Overall, the purpose of this process appears to be to facilitate down-stream [[#Glossary|phosphorylation]] and gene expression regulation(Eg. upregulation of Neuronal Factor Kappa B) via multiple transductive pathways, many of which, are synonymous with tyrosine kinase receptor activity.<ref name=Pat>Patapoutian A, and Reichardt LF. Trk receptors: mediators of neurotrophin action. Current Opinion in Neurobiology 2001; 11:272–280;  Retrieved May 20, 2009, from [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS3-436W778-4&_user=37161&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004218&_version=1&_urlVersion=0&_userid=37161&md5=61e126fa1dabc85ae170386d18189a9c]</ref> Thus, the [[#Glossary|autophosphorylation]] of intracellular domain tyrosine residues precipitates the association of second-messenger adaptor proteins which may or may not themselves be phosphorylated in order to illicit the desired signalling event (Figure 3).
  
  
 
'''co-operation with p75NTR''': Association with p75NTR(also known as the "low affinity neurotropin receptor") appears to be an integral component of regulation of Trk's. This combination of Trk and p75NTR proteins results in the formation of a high-affinity binding site within the Trk binding region, increasing the responsiveness of receptors for thier ligands<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>. Additionally, coordination with p75NTR has been implicated in a reduction in ubiquitination, delay of internalisation of receptors during sensitisation, and overall decreases the apoptotic potential of cell lines <ref>Barker PA. p75NTR is positively promiscuous: novel partners and new insights. Neuron. 2004 May 27;42(4):529-33. Review. Retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/15157416?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum]</ref> .
 
'''co-operation with p75NTR''': Association with p75NTR(also known as the "low affinity neurotropin receptor") appears to be an integral component of regulation of Trk's. This combination of Trk and p75NTR proteins results in the formation of a high-affinity binding site within the Trk binding region, increasing the responsiveness of receptors for thier ligands<ref name=Barker>Barker PA. High affinity not in the vicinity? Neuron. 2007 Jan 4;53(1):1-4. Review retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/17196523] </ref>. Additionally, coordination with p75NTR has been implicated in a reduction in ubiquitination, delay of internalisation of receptors during sensitisation, and overall decreases the apoptotic potential of cell lines <ref>Barker PA. p75NTR is positively promiscuous: novel partners and new insights. Neuron. 2004 May 27;42(4):529-33. Review. Retrieved from [http://www.ncbi.nlm.nih.gov/pubmed/15157416?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum]</ref> .
 
 
  
 
==Mechanism of ''Trk'' Activation via multiple Signalling pathways==
 
==Mechanism of ''Trk'' Activation via multiple Signalling pathways==
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===PLC-y<sub>1</sub> Pathway===
 
===PLC-y<sub>1</sub> Pathway===
  
Phospholipase C, comes in many forms and plays and important role in the signal transduction for many processes, including, proliferation, differentiation and motility. Its main function is to hydrolyze phosphatidylinositoldi phosphate (PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3). <ref name=phdher> PhD, Hershel Raff. Physiology Secrets. Philadelphia: Hanley & Belfus, 2002.</ref>  This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. <ref name=mandk>Mankidy, R., Hastings, J., & Thackeray, J. (2003). Distinct Phospholipase C-#-Dependent Signaling Pathways in the Drosophila Eye and Wing Are Revealed by a New small wing Allele. Genetics Society of America. 164(2): 553–563.</ref>
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Phospholipase C, comes in many forms and plays an important role in the signal transduction for many processes, including proliferation, differentiation and motility. Its main function is to hydrolyze phosphatidylinositoldi phosphate (PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3). <ref name=phdher> PhD, Hershel Raff. Physiology Secrets. Philadelphia: Hanley & Belfus, 2002.</ref>  This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. <ref name=mandk>Mankidy, R., Hastings, J., & Thackeray, J. (2003). Distinct Phospholipase C-#-Dependent Signaling Pathways in the Drosophila Eye and Wing Are Revealed by a New small wing Allele. Genetics Society of America. 164(2): 553–563.</ref>
 
DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein  , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of [[Protein Kinase C]].  <ref name=biothe>Bioengineering; Research from University of Tokyo broadens understanding of bioengineering. (2009,May). Medical Devices & Surgical Technology Week,70.</ref>
 
DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein  , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of [[Protein Kinase C]].  <ref name=biothe>Bioengineering; Research from University of Tokyo broadens understanding of bioengineering. (2009,May). Medical Devices & Surgical Technology Week,70.</ref>
  
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[[Image:Zani1.gif|thumb|10000x10000px|'''Figure 5''': Simplified Animation of PKC pathway. [http://cellbiology.med.unsw.edu.au/cellbiology/images/4/43/Zgifpath.gif Full size animation] ]]
 
[[Image:Zani1.gif|thumb|10000x10000px|'''Figure 5''': Simplified Animation of PKC pathway. [http://cellbiology.med.unsw.edu.au/cellbiology/images/4/43/Zgifpath.gif Full size animation] ]]
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===PKC Pathway===
 
===PKC Pathway===
  
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=User:Z3189925 '''''See also: Protein Kinase C''''']
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=User:Z3189925 '''''See also: Protein Kinase C''''']
  
Protein Kinase C (PKC) is a family of  nucleotide-independent, Ca2+-dependent serine kinases. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>. At least 11 [[#Glossary|isozymes]] have been identified, <ref name=peter>Acs, P., Wang, Q., Bogi, K., Marquez, A., Lorenzo, P., Biro, T., Szallai, Z., Mushinski, F., & Blue, P. (1997). Both the Catalytic and Regulatory Domains of Protein Kinase C Chimeras Modulate the Proliferative Properties of NIH 3T3 Cells. J Biol Chem., 272(45), 28793-28799. Retrieved May 15, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=9353351&dopt=Abstract Pubmed]</ref> most PKC [[#Glossary|isozymes]] are ubiquitous and multiple members of the family can be coexpressed within the same cell leading to complex pathways. However, the basic signal transduction pathway involves the allosteric activation of PKC by the intracellular messengers diacylglycerol and Calcium ions. The inactive PKC is mainly found in the cytosol. Upon stimulation the PKC proteins translocate to the cell membrane. This translocation is the result of a cascade initiated by the binding of a number of extracellular ligands, such as, growth factors, hormones, and neurotransmitters to a G protein-coupled receptor (GPRC) found on the plasma membrane. This in turn activates a stimulating G protein which in turn activates phospholipase C (PLC). <ref name=Dekker>Dekker, L (2004). Protein Kinase C (Molecular Biology Intelligence Unit). New York: Springer.</ref> A G protein is then activated, which then activates phospholipase C (PLC). The PLC cleaves phosphoinositol-4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol-1.,4,5-triphosphate (IP3). <ref name=promega>Signal Transduction Resource. (n.d.). Retrieved May 15, 2009, from [http://www.promega.com/guides/sigtrans_guide/strg_chap03.pdf Promega] </ref> The  IP3, couples to Ca2+ channels found on the endoplasmic reticulum releasing Ca2+ reserves. The increased concentration of calcium ions bind to inactive PKC molecules and then translocates to the plasma membrane. Here is binds to DAG giving rise to the active PKC enzyme. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>  
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Protein Kinase C (PKC) is a family of  nucleotide-independent, Ca2+-dependent serine kinases. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>. At least 11 [[#Glossary|isozymes]] have been identified, <ref name=peter>Acs, P., Wang, Q., Bogi, K., Marquez, A., Lorenzo, P., Biro, T., Szallai, Z., Mushinski, F., & Blue, P. (1997). Both the Catalytic and Regulatory Domains of Protein Kinase C Chimeras Modulate the Proliferative Properties of NIH 3T3 Cells. J Biol Chem., 272(45), 28793-28799. Retrieved May 15, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=9353351&dopt=Abstract Pubmed]</ref> most PKC [[#Glossary|isozymes]] are ubiquitous and multiple members of the family can be coexpressed within the same cell leading to complex pathways. However, the basic signal transduction pathway involves the allosteric activation of PKC by the intracellular messengers diacylglycerol and Calcium ions. The inactive PKC is mainly found in the cytosol. Upon stimulation the PKC proteins translocate to the cell membrane. This translocation is the result of a cascade initiated by the binding of a number of extracellular ligands, such as, growth factors, hormones, and neurotransmitters to a G protein-coupled receptor (GPRC) found on the plasma membrane. This in turn activates a stimulating G protein which in turn activates phospholipase C (PLC). <ref name=Dekker>Dekker, L (2004). Protein Kinase C (Molecular Biology Intelligence Unit). New York: Springer.</ref> A G protein is then activated, which then activates phospholipase C (PLC). The PLC cleaves phosphoinositol-4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol-1.,4,5-triphosphate (IP3). <ref name=promega>Signal Transduction Resource. (n.d.). Retrieved May 15, 2009, from [http://www.promega.com/guides/sigtrans_guide/strg_chap03.pdf Promega] </ref> The  IP3, couples to Ca2+ channels found on the endoplasmic reticulum releasing Ca2+ reserves. The increased concentration of calcium ions bind to inactive PKC molecules and then translocates to the plasma membrane, giving rise to the active PKC enzyme. <ref name=na>Takai, Y., Kishimoto, A., Inoue, M., & Nishizuka, Y. (1977). Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem., 252(21), 7603-7609. [http://www.ncbi.nlm.nih.gov.viviena.library.unsw.edu.au/pubmed/199594?dopt=Abstract] </ref>  
 
The PKC family plays a major role in cellular signal transduction. <ref name=Stein>Steinberg, S. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88, 1341-1378. Retrieved October 5, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=18923184&dopt=Abstract Pubmed]</ref>Their main roles consist in the regulation of cell proliferation, differentiation, survival
 
The PKC family plays a major role in cellular signal transduction. <ref name=Stein>Steinberg, S. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88, 1341-1378. Retrieved October 5, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=18923184&dopt=Abstract Pubmed]</ref>Their main roles consist in the regulation of cell proliferation, differentiation, survival
 
and [[#Glossary|apoptosis]]. <ref name=breit>D Breitkreutz,  L Braiman-Wiksman,  N Daum,  M F Denning,  T Tennenbaum. (2007). Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium. Journal of Cancer Research & Clinical Oncology, 133(11), 793-808.  Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=17661083&dopt=Abstract Pubmed]</ref>
 
and [[#Glossary|apoptosis]]. <ref name=breit>D Breitkreutz,  L Braiman-Wiksman,  N Daum,  M F Denning,  T Tennenbaum. (2007). Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium. Journal of Cancer Research & Clinical Oncology, 133(11), 793-808.  Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=17661083&dopt=Abstract Pubmed]</ref>
 
 
 
 
 
 
  
 
===Ras-MAPK (mitogen-activated protein kinase) Pathway===
 
===Ras-MAPK (mitogen-activated protein kinase) Pathway===
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[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3189168 '''''See also: Phosphatidylinositol 3-kinase''''']
 
[http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3189168 '''''See also: Phosphatidylinositol 3-kinase''''']
  
The role of PI3K is essential in promoting survival of neuronal cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref> PI3K directly activates Ras-dependent pathway through which Trk signaling promotes survival in many, but not all, neurons. Ras-dependent activation of PI3K is the most important pathway through which neurotrophins promote cell survival. In some cells, however, PI3K can also be activated through three adaptor proteins, Shc, Grb-2 and Gab-1. PI3K has an array of main effectors which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are activated either via their interaction with lipid products of PI3K or through PI3K-dependent [[#Glossary|phosphorylation]] of proteins.<ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref> PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. BAD is an important protein in controlling cell survival and is a Bcl-2 family member which promotes [[#Glossary|apoptosis]] by binding to Bcl-xL. When BAD are phosphorylated by Akt or MAPKs, it involves in the regulation of signal transduction in neuronal cells <ref> Stephens LR, Jackson TR, and Hawkins PT. Agonist-stimulated synthesis of phosphatidylinosital(3,4,5)-triphosphate: a new intracellular signaling system? Biochim Biophys Acta 1993;1179(1):27-75. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8399352 Pubmed]</ref> On the other hand, PI3K/Akt signal transduction cascade is predominantly important in the formation of neuronal tumours. This cascade promotes the growth and proliferation of cancer cells and its components represent attractive targets for the design of anticancer agents. mTOR which is a serine/threonine kinase acts on the downstream activation of PI3K for the mediation of prosurvival activity. This will inhibit [[#Glossary|apoptosis]], resulting in the formation of cancer cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref><ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref>
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The role of PI3K is essential in promoting survival of neuronal cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref> PI3K directly activates Ras-dependent pathway through which Trk signaling promotes survival in many, but not all, neurons. In some cells PI3K can be activated through three adaptor proteins, Shc, Grb-2 and Gab-1. PI3K has an array of main effectors, which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are either activated via interaction with lipid products of PI3K or through PI3K-dependent [[#Glossary|phosphorylation]] of proteins.<ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref> PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. BAD is an important protein in controlling cell survival and is a Bcl-2 family member which promotes [[#Glossary|apoptosis]] by binding to Bcl-xL. When BAD are phosphorylated by Akt or MAPKs, it involves in the regulation of signal transduction in neuronal cells <ref> Stephens LR, Jackson TR, and Hawkins PT. Agonist-stimulated synthesis of phosphatidylinosital(3,4,5)-triphosphate: a new intracellular signaling system? Biochim Biophys Acta 1993;1179(1):27-75. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8399352 Pubmed]</ref> On the other hand, PI3K/Akt signal transduction cascade is predominantly important in the formation of neuronal tumours. This cascade promotes the growth and proliferation of cancer cells and its components represent attractive targets for the design of anticancer agents. mTOR which is a serine/threonine kinase acts on the downstream activation of PI3K for the mediation of prosurvival activity. This will inhibit [[#Glossary|apoptosis]], resulting in the formation of cancer cells.<ref name=kr> Krasilnikov MA. Phoshatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/10702641 Pubmed] </ref><ref>Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase. Bioessays. 1994;16(8):565-576. Retrieved May 16, 2009, from [http://www.ncbi.nlm.nih.gov/pubmed/8086005]</ref>
  
 
==Current Research==
 
==Current Research==
  
 
===Cancer biotherapy via targeting ‘Ras / Ras-MAP-kinase’ signalling pathway===
 
===Cancer biotherapy via targeting ‘Ras / Ras-MAP-kinase’ signalling pathway===
Recent studies have hypothesized that receptors responsible for Ras activation would be effective target for treating human cancers<ref name=wip/>Based on this hypothesis, since 1995, therapies utilizing the inhibition of Ras activation have aroused a major interest. Farnesylation is a process by which small G-proteins like Ras are activated and adhered to the cell membrane. In a recent paper <ref name=kohl>Kohl,N.E., Omer C.A., Conner MW., Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP., Graham SL., Hamilton K., “Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice”. Nat Med (1995).1(8): 792-7. </ref>, [[#Glossary|farnesyl transferase inhibitors]] were used in order to block the farnesylation of Ras proteins. The results revealed promising hopes in animal models but unfortunately have not been effective in human cancer treatment.<ref name=kohl/> The major downstream target of Ras-MAP-Kinase (MAPK) has also been taken as a subject for drug design. Sebolt and his colleagues showed that MAPK-inhibitors are effective in cancer therapy using mouse models <ref name=sebol> Sebolt,J.S,. Dudley D.T,. Herrera.R, Van Becelaere.K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski.S,. Leopold WR. Saltiel A.R,. “Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo”. Nat Med. (1999).5(7): 810-6.</ref> . It has been also suggested that Inhibition of the Ras-MAPK signaling pathway can serve as a potential therapy for NF1 in humans. <ref name=sep> Sebti S.M., Hamilton A.D,. “Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies”. Oncogene.(2000).19(56): 6584-93.</ref>
+
Recent studies have hypothesized that receptors responsible for Ras activation would be effective target for treating human cancers<ref name=wip/>. Based on this hypothesis, since 1995, therapies utilizing the inhibition of Ras activation have aroused a major interest. Farnesylation is a process by which small G-proteins like Ras are activated and adhered to the cell membrane. In a recent paper <ref name=kohl>Kohl,N.E., Omer C.A., Conner MW., Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP., Graham SL., Hamilton K., “Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice”. Nat Med (1995).1(8): 792-7. </ref>, [[#Glossary|farnesyl transferase inhibitors]] were used in order to block the farnesylation of Ras proteins. The results revealed promising hopes in animal models but unfortunately have not been effective in human cancer treatment<ref name=kohl/>. The major downstream target of Ras-MAP-Kinase (MAPK) has also been taken as a subject for drug design. Sebolt and his colleagues showed that MAPK-inhibitors are effective in cancer therapy using mouse models <ref name=sebol> Sebolt,J.S,. Dudley D.T,. Herrera.R, Van Becelaere.K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski.S,. Leopold WR. Saltiel A.R,. “Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo”. Nat Med. (1999).5(7): 810-6.</ref> . It has been also suggested that Inhibition of the Ras-MAPK signaling pathway can serve as a potential therapy for NF1 in humans. <ref name=sep> Sebti S.M., Hamilton A.D,. “Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies”. Oncogene.(2000).19(56): 6584-93.</ref>
  
 
===''Trk'' receptors can behave as signalling endosomes===
 
===''Trk'' receptors can behave as signalling endosomes===
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===The interplay between miRNA and ''Trk''s (''tropomyosin-related kinases'')===
 
===The interplay between miRNA and ''Trk''s (''tropomyosin-related kinases'')===
  
MicroRNAs are tissue specific, small non-coding RNAs, which are involved in post-trancriptional-silencing mechanism ([http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3191358'''''See also: miRNA Science Overview''''']). In non-mammals, miRNAs have been discovered to be involved in developmental process of the nervous system. For instance, in Caenorhabditis elegans, miR-273 participate in a regulatory mechanism in which ensures for the morphgenesis and differentiation of receptor neurons. <ref name=smip>Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. “Regulation of miRNA expression during neural cell specification”. Eur J Neurosci. 2005;21(6):1469-77</ref>
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MicroRNAs are tissue specific, small non-coding RNAs, which are involved in post-trancriptional-silencing mechanism ([http://cellbiology.med.unsw.edu.au/cellbiology/index.php?title=3191358'''''See also: miRNA Science Overview''''']). In non-mammals, miRNAs have been discovered to be involved in developmental process of the nervous system. For instance, in ''Caenorhabditis elegans'', miR-273 participate in a regulatory mechanism in which ensures for the morphgenesis and differentiation of receptor neurons. <ref name=smip>Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. “Regulation of miRNA expression during neural cell specification”. Eur J Neurosci. 2005;21(6):1469-77</ref>
Likewise, in mammalian brain tissue, recent studies show that certain miRNAs have been identified, in which suggest an important role of these small molecules in modulating Trk receptors and development of nervous system. In addition, functional regulation of these miRNAs is also linked to tumorgenesis of nervous system. For instance, three neuronal miRNAs (9,125a and 125b) are found to be involved in human neuroblastoma cell proliferation by down-modulating TrkC isoform. <ref name=miska>Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. “Microarray analysis of microRNA expression in the developing mammalian brain”. Genome Biol. 2004;5(9):R68 </ref>
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Likewise, in mammalian brain tissue certain miRNAs have been identified, in which suggest an important role of these small molecules in modulating Trk receptors and development of nervous system. In addition, functional regulation of these miRNAs is also linked to tumorgenesis of nervous system. For instance, three neuronal miRNAs (9,125a and 125b) are found to be involved in human neuroblastoma cell proliferation by down-modulating TrkC isoform. <ref name=miska>Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. “Microarray analysis of microRNA expression in the developing mammalian brain”. Genome Biol. 2004;5(9):R68 </ref>
  
 
==Glossary==
 
==Glossary==
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== 2009 Group Projects ==
 
--[[User:S8600021|Mark Hill]] 14:02, 19 March 2009 (EST) Please leave these links to all group projects at the bottom of your project page.
 
  
[[2009 Group 1 Project|Group 1 Meiosis]] |
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{{Template:2009_Group_Projects}}
[[2009 Group 2 Project|Group 2 Cell Death - Apoptosis]] |
 
[[2009 Group 3 Project|Group 3 Cell Division]] |
 
[[2009 Group 4 Project|Group 4 Trk Receptors]] |
 
[[2009 Group 5 Project|Group 5 The Cell Cycle]] |
 
[[2009 Group 6 Project|Group 6 Golgi Apparatus]] |
 
[[2009 Group 7 Project|Group 7 Mitochondria]] |
 
[[2009 Group 8 Project|Group 8 Cell Death - Necrosis]] |
 
[[2009 Group 9 Project|Group 9 Nucleus]] |
 
[[2009 Group 10 Project|Group 10 Cell Shape]]
 

Latest revision as of 14:30, 18 November 2009

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