The Experts below are selected from a list of 15408 Experts worldwide ranked by ideXlab platform
Evan T Keller - One of the best experts on this subject based on the ideXlab platform.
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survey of Raf Kinase inhibitor protein rkip in multiple cancer types
Critical Reviews in Oncogenesis, 2014Co-Authors: Kelly Lamiman, Jill M Keller, Atsushi Mizokami, Jian Zhang, Evan T KellerAbstract:Raf Kinase inhibitor protein (RKIP), an inhibitor of several signaling pathways, has been shown to have metastasis suppressor gene activity and promote apoptosis. While first identified in prostate cancer, RKIP's anti-metastasis properties have now been demonstrated in multiple tumor types. Furthermore, loss of RKIP expression is observed in many cancers as they progress. In this review, we provide a survey of the many tumor types in which RKIP function or expression has been evaluated. Particular attention is focused on the expression of RKIP in clinical tissues and its prognostic significance. A PubMed search through May 2014 identified 56 publications detailing RKIP expression in clinical cancer tissues. The majority of studies revealed that loss of RKIP expression has prognostic value for overall survival, disease free survival, and presence of metastasis for most solid tumor cancers; whereas, RKIP expression correlated with tumor grade or stage in approximately only 50% of the publications. In summary, RKIP loss is a frequent occurrence in many solid tumor cancers and may serve as a viable prognostic biomarker.
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Raf Kinase inhibitor protein rkip in cancer
Cancer and Metastasis Reviews, 2012Co-Authors: June Escarawilke, Kam C Yeung, Evan T KellerAbstract:Raf Kinase inhibitory protein (RKIP) was initially identified as phosphatidylethanolamine binding protein in bovine brain. It was later identified as a protein that inhibits Raf Kinase activation of MEK. Further exploration has revealed that RKIP modulates several other signaling pathways including NF–κB and G-protein signaling. A gene array screen revealed that RKIP expression was low in a metastatic compared with non-metastatic prostate cancer cell line. Further experiments revealed that RKIP fits the criteria for a metastasis suppressor gene. RKIP expression has been shown to be downregulated in metastatic tissues, compared with non-metastatic tissue in multiple cancers, suggesting that loss of RKIP metastasis suppressor activity is a broad mechanism leading to metastasis. Additionally, loss of RKIP has been shown to impact therapy through conferring radioresistance and chemoresistance. Taken together, these data indicate understanding RKIP’s contributions to cancer may lead to important therapeutic strategies to prevent metastasis and promote therapeutic efficacy.
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The biology of a prostate cancer metastasis suppressor protein: Raf Kinase inhibitor protein
Journal of Cellular Biochemistry, 2005Co-Authors: Evan T Keller, Zheng Fu, Meghan BrennanAbstract:Raf Kinase inhibitor protein (RKIP) was originally identified as a protein that bound membrane phospholipids and was named phosphatidylethanolamine binding protein-2 (PEBP-2). RKIP was than identified as a protein that bound Raf and blocked its ability to phosphorylate MEK, thus earning its new name of RKIP. Subsequent to identificationofitsroleintheRaf:MEKpathway,RKIPhasbeendemonstratedtoregulateseveralothersignalingpathways includingG-proteinsignalingandNF-kBsignaling.ItsinvolvementinseveralsignalingpathwayshasengenderedRKIPto contribute to several physiological processes including membrane biosynthesis, spermatogenesis, neural development, andapoptosis.RKIPisexpressedinmanytissuesincludingbrain,lung,andliverandthus,dysregulationofRKIPexpression orfunction has potential to contribute to pathophysiology in these tissues. Lossof RKIP expression in prostatecancer cells confers a metastatic phenotype on them. Additionally, restoration of RKIP expression in a metastatic prostate cancer cell linedoesnoteffectprimarytumorgrowth,butitdoesinhibitprostatecancermetastasis.TheseparametersidentifyRKIPas a metastasis suppressor gene. In this review, the biology and pathophysiology of RKIP is described. J. Cell. Biochem. 94: 273-278, 2005. 2004 Wiley-Liss, Inc.
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the biology of a prostate cancer metastasis suppressor protein Raf Kinase inhibitor protein
Journal of Cellular Biochemistry, 2005Co-Authors: Evan T Keller, Meghan BrennanAbstract:Raf Kinase inhibitor protein (RKIP) was originally identified as a protein that bound membrane phospholipids and was named phosphatidylethanolamine binding protein-2 (PEBP-2). RKIP was than identified as a protein that bound Raf and blocked its ability to phosphorylate MEK, thus earning its new name of RKIP. Subsequent to identification of its role in the Raf:MEK pathway, RKIP has been demonstrated to regulate several other signaling pathways including G-protein signaling and NF-kappaB signaling. Its involvement in several signaling pathways has engendered RKIP to contribute to several physiological processes including membrane biosynthesis, spermatogenesis, neural development, and apoptosis. RKIP is expressed in many tissues including brain, lung, and liver and thus, dysregulation of RKIP expression or function has potential to contribute to pathophysiology in these tissues. Loss of RKIP expression in prostate cancer cells confers a metastatic phenotype on them. Additionally, restoration of RKIP expression in a metastatic prostate cancer cell line does not effect primary tumor growth, but it does inhibit prostate cancer metastasis. These parameters identify RKIP as a metastasis suppressor gene. In this review, the biology and pathophysiology of RKIP is described.
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the role of Raf Kinase inhibitor protein rkip in health and disease
Biochemical Pharmacology, 2004Co-Authors: Evan T Keller, Meghan BrennanAbstract:Raf Kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding protein (PEBP) family. RKIP plays a pivotal modulatory role in several protein Kinase signaling cascades. RKIP binds inhibits Raf-1-mediated phosphorylation of MEK through binding to Raf-1. Protein Kinase C (PKC) phosphorylates RKIP, resulting in release of Raf-1 and activation of MEK and ERK. The phosphorylated RKIP binds to and inhibits G-protein-coupled receptor Kinase, resulting in sustained G-protein signaling. The regulatory role that RKIP has in cell signaling is reflected in its role in physiology and pathophysiology. RKIP is involved in neural development, cardiac function and spermatogenesis and appears to have serine protease activity. In addition to its roles in physiology, dysregulated RKIP expression has the potential to contribute to pathophysiological processes including Alzheimer's disease and diabetic nephropathy. RKIP has been shown to fit the criteria of being a metastasis suppressor gene, including having decreased expression in prostate cancer metastases and restoring RKIP expression in a prostate cancer cell line diminishes metastasis in a murine model. Clearly, RKIP has multiple molecular and cellular functions. In this review, RKIP's molecular roles in intracellular signaling, its physiological functions and its role in disease are described.
Marsha Rich Rosner - One of the best experts on this subject based on the ideXlab platform.
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Function of BACH1 as a key target of RKIP in breast cancer
Prognostic and Therapeutic Applications of RKIP in Cancer, 2020Co-Authors: Marsha Rich Rosner, Jiyoung LeeAbstract:Abstract Raf Kinase inhibitory protein (RKIP; PEBP1) is a metastasis suppressor. Understanding the mechanism by which RKIP inhibits metastasis reveals key pro-metastatic genes. One of these, the transcription factor BACH1, is negatively regulated by RKIP and itself has multiple functions that promote invasion and metastasis as well as aerobic glycolysis, a characteristic of tumor cell metabolism. Here we summarize some of the pro-metastatic properties of BACH1 and a new therapeutic strategy targeting BACH1 involving repurposing of metabolic inhibitors.
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Raf Kinase inhibitory protein suppresses a metastasis signalling cascade involving lin28 and let 7
The EMBO Journal, 2009Co-Authors: Surabhi Dangigarimella, Eva M Eves, Martin A Newman, Stefan J Erkeland, Scott M Hammond, Andy J Minn, Marsha Rich RosnerAbstract:Raf Kinase inhibitory protein (RKIP) negatively regulates the MAP Kinase (MAPK), G protein-coupled receptor Kinase-2, and NF-κB signalling cascades. RKIP has been implicated as a metastasis suppressor for prostate cancer, but the mechanism is not known. Here, we show that RKIP inhibits invasion by metastatic breast cancer cells and represses breast tumour cell intravasation and bone metastasis in an orthotopic murine model. The mechanism involves inhibition of MAPK, leading to decreased transcription of LIN28 by Myc. Suppression of LIN28 enables enhanced let-7 processing in breast cancer cells. Elevated let-7 expression inhibits HMGA2, a chromatin remodelling protein that activates pro-invasive and pro-metastatic genes, including Snail. LIN28 depletion and let-7 expression suppress bone metastasis, and LIN28 restores bone metastasis in mice bearing RKIP-expressing breast tumour cells. These results indicate that RKIP suppresses invasion and metastasis in part through a signalling cascade involving MAPK, Myc, LIN28, let-7, and downstream let-7 targets. RKIP regulation of two pluripotent stem cell genes, Myc and LIN28, highlights the importance of RKIP as a key metastasis suppressor and potential therapeutic agent.
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Raf Kinase inhibitory protein (RKIP): a physiological regulator and future therapeutic target.
Expert Opinion on Therapeutic Targets, 2008Co-Authors: Lingchun Zeng, Akira Imamoto, Marsha Rich RosnerAbstract:BACKGROUND: Raf Kinase inhibitory protein (RKIP) belongs to the phosphatidylethanolamine binding protein (PEBP) family that is expressed in both prokaryotic and euakaryotic organisms. OBJECTIVE: In this review, we discuss the role of RKIP as a modulator of signal transduction, the relationship of RKIP to other members of the PEBP family, and the role of RKIP in human health and disease. RESULTS/CONCLUSION: In mammals, RKIP regulates activation of MAPK, NF-kappaB and G protein coupled receptors (GPCRs). As a modulator of key signaling pathways, RKIP affects various cellular processes including cell differentiation, the cell cycle, apoptosis and cell migration. Emerging evidence suggests that RKIP is implicated in several human diseases or disorders, among them metastatic tumorigenesis and Alzheimer's disease.
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Raf Kinase inhibitory protein: a signal transduction modulator and metastasis suppressor
Cell Research, 2008Co-Authors: Alexey E Granovsky, Marsha Rich RosnerAbstract:Cells have a multitude of controls to maintain their integrity and prevent random switching from one biological state to another. Raf Kinase Inhibitory Protein (RKIP), a member of the phosphatidylethanolamine binding protein (PEBP) family, is representative of a new class of modulators of signaling cascades that function to maintain the “yin yang” or balance of biological systems. RKIP inhibits MAP Kinase (Raf-MEK-ERK), G protein-coupled receptor (GPCR) Kinase and NFκB signaling cascades. Because RKIP targets different Kinases dependent upon its state of phosphorylation, RKIP also acts to integrate crosstalk initiated by multiple environmental stimuli. Loss or depletion of RKIP results in disruption of the normal cellular stasis and can lead to chromosomal abnormalities and disease states such as cancer. Since RKIP and the PEBP family have been reviewed previously, the goal of this analysis is to provide an update and highlight some of the unique features of RKIP that make it a critical player in the regulation of cellular signaling processes.
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MAP Kinase meets mitosis: A role for Raf Kinase Inhibitory Protein in spindle checkpoint regulation
Cell Division, 2007Co-Authors: Marsha Rich RosnerAbstract:Raf Kinase Inhibitory Protein (RKIP) is an evolutionarily conserved protein that functions as a modulator of signaling by the MAP Kinase cascade. Implicated as a metastasis suppressor, Raf Kinase Inhibitory Protein depletion correlates with poor prognosis for breast, prostate and melanoma tumors but the mechanism is unknown. Recent evidence indicates that Raf Kinase Inhibitory Protein regulates the mitotic spindle assembly checkpoint by controlling Aurora B Kinase activity, and the mechanism involves Raf/MEK/ERK signaling. In contrast to elevated MAP Kinase signaling during the G1, S or G2 phases of the cell cycle that activates checkpoints and induces arrest or senescence, loss of RKIP during M phase leads to bypass of the spindle assembly checkpoint and the generation of chromosomal abnormalities. These results reveal a role for Raf Kinase Inhibitory Protein and the MAP Kinase cascade in ensuring the fidelity of chromosome segregation prior to cell division. Furthermore, these data highlight the need for precise titration of the MAP Kinase signal to ensure the integrity of the spindle assembly process and provide a mechanism for generating genomic instability in tumors. Finally, these results raise the possibility that RKIP status in tumors could influence the efficacy of treatments such as poisons that stimulate the Aurora B-dependent spindle assembly checkpoint.
Meghan Brennan - One of the best experts on this subject based on the ideXlab platform.
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The biology of a prostate cancer metastasis suppressor protein: Raf Kinase inhibitor protein
Journal of Cellular Biochemistry, 2005Co-Authors: Evan T Keller, Zheng Fu, Meghan BrennanAbstract:Raf Kinase inhibitor protein (RKIP) was originally identified as a protein that bound membrane phospholipids and was named phosphatidylethanolamine binding protein-2 (PEBP-2). RKIP was than identified as a protein that bound Raf and blocked its ability to phosphorylate MEK, thus earning its new name of RKIP. Subsequent to identificationofitsroleintheRaf:MEKpathway,RKIPhasbeendemonstratedtoregulateseveralothersignalingpathways includingG-proteinsignalingandNF-kBsignaling.ItsinvolvementinseveralsignalingpathwayshasengenderedRKIPto contribute to several physiological processes including membrane biosynthesis, spermatogenesis, neural development, andapoptosis.RKIPisexpressedinmanytissuesincludingbrain,lung,andliverandthus,dysregulationofRKIPexpression orfunction has potential to contribute to pathophysiology in these tissues. Lossof RKIP expression in prostatecancer cells confers a metastatic phenotype on them. Additionally, restoration of RKIP expression in a metastatic prostate cancer cell linedoesnoteffectprimarytumorgrowth,butitdoesinhibitprostatecancermetastasis.TheseparametersidentifyRKIPas a metastasis suppressor gene. In this review, the biology and pathophysiology of RKIP is described. J. Cell. Biochem. 94: 273-278, 2005. 2004 Wiley-Liss, Inc.
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the biology of a prostate cancer metastasis suppressor protein Raf Kinase inhibitor protein
Journal of Cellular Biochemistry, 2005Co-Authors: Evan T Keller, Meghan BrennanAbstract:Raf Kinase inhibitor protein (RKIP) was originally identified as a protein that bound membrane phospholipids and was named phosphatidylethanolamine binding protein-2 (PEBP-2). RKIP was than identified as a protein that bound Raf and blocked its ability to phosphorylate MEK, thus earning its new name of RKIP. Subsequent to identification of its role in the Raf:MEK pathway, RKIP has been demonstrated to regulate several other signaling pathways including G-protein signaling and NF-kappaB signaling. Its involvement in several signaling pathways has engendered RKIP to contribute to several physiological processes including membrane biosynthesis, spermatogenesis, neural development, and apoptosis. RKIP is expressed in many tissues including brain, lung, and liver and thus, dysregulation of RKIP expression or function has potential to contribute to pathophysiology in these tissues. Loss of RKIP expression in prostate cancer cells confers a metastatic phenotype on them. Additionally, restoration of RKIP expression in a metastatic prostate cancer cell line does not effect primary tumor growth, but it does inhibit prostate cancer metastasis. These parameters identify RKIP as a metastasis suppressor gene. In this review, the biology and pathophysiology of RKIP is described.
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the role of Raf Kinase inhibitor protein rkip in health and disease
Biochemical Pharmacology, 2004Co-Authors: Evan T Keller, Meghan BrennanAbstract:Raf Kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding protein (PEBP) family. RKIP plays a pivotal modulatory role in several protein Kinase signaling cascades. RKIP binds inhibits Raf-1-mediated phosphorylation of MEK through binding to Raf-1. Protein Kinase C (PKC) phosphorylates RKIP, resulting in release of Raf-1 and activation of MEK and ERK. The phosphorylated RKIP binds to and inhibits G-protein-coupled receptor Kinase, resulting in sustained G-protein signaling. The regulatory role that RKIP has in cell signaling is reflected in its role in physiology and pathophysiology. RKIP is involved in neural development, cardiac function and spermatogenesis and appears to have serine protease activity. In addition to its roles in physiology, dysregulated RKIP expression has the potential to contribute to pathophysiological processes including Alzheimer's disease and diabetic nephropathy. RKIP has been shown to fit the criteria of being a metastasis suppressor gene, including having decreased expression in prostate cancer metastases and restoring RKIP expression in a prostate cancer cell line diminishes metastasis in a murine model. Clearly, RKIP has multiple molecular and cellular functions. In this review, RKIP's molecular roles in intracellular signaling, its physiological functions and its role in disease are described.
Ulf R Rapp - One of the best experts on this subject based on the ideXlab platform.
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role of melanoma inhibitor of apoptosis ml iap protein a member of the baculoviral iap repeat bir domain family in the regulation of c Raf Kinase and cell migration
Journal of Biological Chemistry, 2012Co-Authors: Tripat Kaur Oberoikhanuja, Ulf R Rapp, Christiaan Karreman, Sarit Larisch, Krishnaraj RajalingamAbstract:Abstract SUMMARY Inhibitors of Apoptosis (IAPs) proteins are characterized by the presence of evolutionarily conserved Baculoviral Inhibitor of Apoptosis Repeat (BIR) domains, predominantly known for their role in inhibiting caspases and thereby apoptosis. We have previously shown that multi-BIR domain containing IAPs, cIAPs and XIAP can control tumour cell migration by directly regulating the protein stability of C-Raf Kinase. Here, we extend our observations to a single BIR domain containing IAP family member, Melanoma-IAP (ML-IAP). We show that ML-IAP can directly bind to C-Raf and ML-IAP depletion leads to an increase in C-Raf protein levels, MAPK activation and cell migration in melanoma cells. Thus, our results unveil a thus far unknown role for ML-IAP in controlling C-Raf stability and cell migration.
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Raf Kinase activity regulates neuroepithelial cell proliferation and neuronal progenitor cell differentiation during early inner ear development
PLOS ONE, 2010Co-Authors: Ulf R Rapp, Marta Magarinos, Maria Rodriguez Aburto, Hortensia Sanchezcalderon, Carmen Munozagudo, Isabel VarelanietoAbstract:Background Early inner ear development requires the strict regulation of cell proliferation, survival, migration and differentiation, coordinated by the concerted action of extrinsic and intrinsic factors. Deregulation of these processes is associated with embryonic malformations and deafness. We have shown that insulin-like growth factor I (IGF-I) plays a key role in embryonic and postnatal otic development by triggering the activation of intracellular lipid and protein Kinases. Raf Kinases are serine/threonine Kinases that regulate the highly conserved RAS-Raf-MEK-ERK signaling cascade involved in transducing the signals from extracellular growth factors to the nucleus. However, the regulation of Raf Kinase activity by growth factors during development is complex and still not fully understood.
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use of mitogenic cascade blockers for treatment of c Raf induced lung adenoma in vivo ci 1040 strongly reduces growth and improves lung structure
BMC Cancer, 2004Co-Authors: Boris W. Kramer, Rudolf Gotz, Ulf R RappAbstract:Background: Signaling networks promoting cell growth and proliferation are frequently deregulated in cancer. Tumors often are highly dependent on such signaling pathways and may become hypersensitive to downregulation of key components within these signaling cascades. The classical mitogenic cascade transmits stimuli from growth factor receptors via Ras, Raf, MEK and ERK to the cell nucleus and provides attractive molecular targets for cancer treatment. For example, Ras and Raf Kinase inhibitors are already in a number of ongoing phase II and phase III clinical trials. In this study the effect of the Raf Kinase inhibitor BAY 43-9006 and of the MEK inhibitor CI-1040 (PD184352) on a Raf dependent lung tumor mouse model was analyzed in detail. Methods: We have generated a lung cancer mouse model by targeting constitutively active C-Raf Kinase to the lung. These mice develop adenomas within 4 months of life. At this time-point they received daily intraperitoneal injections of either 100 mg/kg BAY 43-9006 or CI-1040 for additional 21 days. Thereafter, lungs were isolated and the following parameters were analyzed using histology and immunohistochemistry: overall lung structure, frequency of adenoma foci, proliferation rate, ERK activity, caspase-3 activation, and lung differentiation. Results: Both inhibitors were equally effective in vitro using a sensitive Raf/MEK/ERK ELISA. In vivo, the systemic administration of the MEK inhibitor CI-1040 reduced adenoma formation to a third and significantly restored lung structure. The proliferation rate of lung cells of mice treated with CL-1040 was decreased without any obvious effects on differentiation of pneumocytes. In contrast, the Raf inhibitor BAY 43-9006 did not influence adenoma formation in vivo. Conclusion: The MEK inhibitor CI-1040 may be used for the treatment of Ras and/or Rafdependent human malignancies.
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role of diacylglycerol regulated protein Kinase c isotypes in growth factor activation of the Raf 1 protein Kinase
Molecular and Cellular Biology, 1997Co-Authors: U Smola, Ulf R Rapp, Jorge Moscat, V Wixler, I Eisenmanntappe, M T Diazmeco, Geoffrey M. CooperAbstract:The Raf protein Kinases function downstream of Ras guanine nucleotide-binding proteins to transduce intracellular signals from growth factor receptors. Interaction with Ras recruits Raf to the plasma membrane, but the subsequent mechanism of Raf activation has not been established. Previous studies implicated hydrolysis of phosphatidylcholine (PC) in Raf activation; therefore, we investigated the role of the «isotype of protein Kinase C (PKC), which is stimulated by PC-derived diacylglycerol, as a Raf activator. A dominant negative mutant of PKC« inhibited both proliferation of NIH 3T3 cells and activation of Raf in COS cells. Conversely, overexpression of active PKC« stimulated Raf Kinase activity in COS cells and overcame the inhibitory effects of dominant negative Ras in NIH 3T3 cells. PKC«also stimulated Raf Kinase in baculovirusinfected Spodoptera frugiperda Sf9 cells and was able to directly activate Raf in vitro. Consistent with its previously reported activity as a Raf activator in vitro, PKCafunctioned similarly to PKC«in both NIH 3T3 and COS cell assays. In addition, constitutively active mutants of both PKCa and PKC« overcame the inhibitory effects of dominant negative mutants of the other PKC isotype, indicating that these diacylglycerolregulated PKCs function as redundant activators of Raf-1 in vivo.
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role of diacylglycerol regulated protein Kinase c isotypes in growth factor activation of the Raf 1 protein Kinase
Molecular and Cellular Biology, 1997Co-Authors: Hong Cai, Ulf R Rapp, Jorge Moscat, U Smola, V Wixler, I Eisenmanntappe, M T Diazmeco, Geoffrey M. CooperAbstract:The Raf protein Kinases function downstream of Ras guanine nucleotide-binding proteins to transduce intracellular signals from growth factor receptors. Interaction with Ras recruits Raf to the plasma membrane, but the subsequent mechanism of Raf activation has not been established. Previous studies implicated hydrolysis of phosphatidylcholine (PC) in Raf activation; therefore, we investigated the role of the epsilon isotype of protein Kinase C (PKC), which is stimulated by PC-derived diacylglycerol, as a Raf activator. A dominant negative mutant of PKC epsilon inhibited both proliferation of NIH 3T3 cells and activation of Raf in COS cells. Conversely, overexpression of active PKC epsilon stimulated Raf Kinase activity in COS cells and overcame the inhibitory effects of dominant negative Ras in NIH 3T3 cells. PKC epsilon also stimulated Raf Kinase in baculovirus-infected Spodoptera frugiperda Sf9 cells and was able to directly activate Raf in vitro. Consistent with its previously reported activity as a Raf activator in vitro, PKC alpha functioned similarly to PKC epsilon in both NIH 3T3 and COS cell assays. In addition, constitutively active mutants of both PKC alpha and PKC epsilon overcame the inhibitory effects of dominant negative mutants of the other PKC isotype, indicating that these diacylglycerol-regulated PKCs function as redundant activators of Raf-1 in vivo.
Fahd Almulla - One of the best experts on this subject based on the ideXlab platform.
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Raf Kinase inhibitor protein rkip blocks signal transducer and activator of transcription 3 stat3 activation in breast and prostate cancer
PLOS ONE, 2014Co-Authors: Saad Yousuf, Benjamin Bonavida, Kam C Yeung, Meili Duan, Erika L Moen, Sam Crossknorr, Kate E Brilliant, Theresa Lavalle, Fahd AlmullaAbstract:Raf Kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding-protein (PEBP) family that modulates the action of many Kinases involved in cellular growth, apoptosis, epithelial to mesenchymal transition, motility, invasion and metastasis. Previously, we described an inverse association between RKIP and signal transducers and activators of transcription 3 (STAT3) expression in gastric adenocarcinoma patients. In this study, we elucidated the mechanism by which RKIP regulates STAT3 activity in breast and prostate cancer cell lines. RKIP over expression inhibited c-Src auto-phosphorylation and activation, as well as IL-6-, JAK1 and 2-, and activated Raf-mediated STAT3 tyrosine and serine phosphorylation and subsequent activation. In MDA-231 breast cancer cells that stably over express RKIP, IL-6 treatment blocked STAT3 phosphorylation and transcriptional activation. Conversely, in RKIP knockdown MDA-231 cells: STAT3 phosphorylation and activation increased in comparison to parental MDA-231 cells. RKIP over expression resulted in constitutive physical interaction with STAT3 and blocked c-Src and STAT3 association. The treatment of DU145 prostate, but not PC3 prostate or MDA-231 breast, cancer cell lines with ENMD-1198 or MKC-1 dramatically increased expression of RKIP. Overexpression of RKIP sensitized PC3 and MDA-231 cells to MTI-induced apoptosis. Moreover, MTI treatment resulted in a decrease in Src-mediated STAT3 tyrosine phosphorylation and activation, an effect that was significantly enhanced by RKIP over expression. In stable RKIP over expressing MDA-231 cells, tumor xenogRaft growth induced by activated STAT3 is inhibited. RKIP synergizes with MTIs to induce apoptosis and inhibit STAT3 activation of breast and prostate cancer cells. RKIP plays a critical role in opposing the effects of pro-oncogenic STAT3 activation.
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rkip much more than Raf Kinase inhibitory protein
Journal of Cellular Physiology, 2013Co-Authors: Fahd Almulla, Milad S Bitar, Zainab Taqi, Kam C YeungAbstract:From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf Kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease.
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Raf Kinase inhibitor protein expression combined with peritoneal involvement and lymphovascular invasion predicts prognosis in dukes b colorectal cancer patients
Histopathology, 2013Co-Authors: Brendan Doyle, Suzanne Hagan, Fahd Almulla, Lucy Scott, Graeme I Murray, Sharon Harden, J Paul, Hugh Mulcahy, Kieran Sheahan, Jacintha OsullivanAbstract:Aims There is controversy regarding the use of adjuvant therapy in patients with Dukes' B colorectal cancer (CRC). New markers, identifying high-risk Dukes' B patients, are needed. Here, we examine the utility of Raf Kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation. Methods and results We used a tissue microarray of 220 patients with Dukes' B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status. RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator, along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing. Conclusions Raf Kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes' B CRC patients. This demonstrates the potential utility of RKIP in identifying ‘high-risk’ Dukes' B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy.
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Raf Kinase inhibitor protein rkip enhances signaling by glycogen synthase Kinase 3β
Cancer Research, 2011Co-Authors: Fahd Almulla, Abdulla Behbehani, Milad S Bitar, Brendan Doyle, May Almaghrebi, Waleed Alali, Oliver Rath, Kit Yee Tan, Andrew R Pitt, Walter KolchAbstract:Raf Kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-Raf Kinase and nuclear factor ?B signaling that represses tumor invasion and metastasis. Glycogen synthase Kinase-3s (GSK3s) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3s protein levels and its active form. Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein Kinase, which, in turn, inactivates GSK3s by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3s inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and s-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3s expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression.
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Raf Kinase inhibitor protein mechanism of loss of expression and association with genomic instability
Journal of Clinical Pathology, 2008Co-Authors: Fahd Almulla, Suzanne Hagan, Abdulla Behbehani, Milad S Bitar, Waleed Alali, Sindhu Jacob, Ashraf Dallol, Walter KolchAbstract:Aims: Raf Kinase inhibitory protein (RKIP; also known as PEBP, for phosphatidylethanolamine-binding protein) is an endogenous inhibitor of the Raf– MAPK Kinase (MEK)–MAP Kinase pathway. It has emerged as a significant metastasis suppressor in a variety of human cancers including colorectal cancer (CRC) and was recently shown to regulate the spindle checkpoint in cultured cells. This study aims at correlating RKIP expression with chromosomal instability in colorectal cancer samples and identifies possible mechanisms of RKIP loss. Methods: Chromosomal instability was assessed using metaphase-based comparative genomic hybridisation (CGH) and loss of heterozygosity (LOH) in 65 cases with microsatellite stable CRC and correlated with RKIP expression. Methyl-specific PCR was used on DNA extracted from 82 cases with CRC to determine CpG methylation status at the RKIP promoter and the results correlated with RKIP protein expression. Results: We demonstrate for the first time that in microsatellite stable (MSS) CRC, the number of chromosomal losses is inversely proportional to RKIP expression levels. We also show that methylation of the RKIP promoter is a major mechanism by which RKIP expression is silenced in CRC. Conclusions: RKIP loss by hypermethylation of its promoter could have a significant influence on colorectal cancer aneuploidy, which might explain its association with metastatic progression.
