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Fuyu Chueh - One of the best experts on this subject based on the ideXlab platform.
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abstract 4008 nuclear localization of lymphocyte specific protein tyrosine kinase lck and its role in regulating lim domain only 2 lmo2 gene
Cancer Research, 2012Co-Authors: Srividya Venkitachalam, Fuyu ChuehAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lmo2 is a transcription factor that plays a critical role in both hematopoietic development and vascular remodeling. Lmo2 - associated chromosomal translocations are believed to play a major role in the development of T-cell acute lymphoblastic leukemia (T-ALL). Lmo2 is also shown to interact with the T-cell acute lymphocytic leukemia protein (TAL1) in leukemia. A previous report established a link between Lmo2 expression and the unexpected nuclear presence of Oncogenic Janus kinase 2 (JAK2), a non-receptor protein tyrosine kinase. However, it is not known whether other Oncogenic tyrosine kinases regulate Lmo2 expression through a similar mechanism. We showed previously that Oncogenic Lck kinase promotes cellular transformation through the activation of signal transducer and activator of transcription 5b (Mol Cancer Res 4:39). In this report, we describe novel nuclear localization of Lck and its role in regulating Lmo2 expression. Lck, like most Src family kinases, is primarily known as a cytosolic or membrane-associated kinase. Using subcellular fractionation and immunofluorescence microscopy, we identified nuclear localization of Lck in murine leukemia cells (LSTRA) that overexpress Lck kinase. Nuclear Lck was also detected in 293 cells expressing constitutively active Y505FLck. Additionally, phosphorylation of the positive-regulatory tyrosine 394 confirmed the active status of nuclear Lck. These data suggest that Oncogenic Lck may have an uncharacterized function within the nucleus that supports cellular transformation. Lmo2 expression was significantly elevated both in LSTRA leukemia and in 293 cells expressing Oncogenic Y505FLck kinase. The Oncogenic JAK2 kinase phosphorylates histone H3 on Y41 that leads to the relief of Lmo2 promoter repression and subsequent gene expression. However, expression of Oncogenic Lck kinase does not result in significant increase in H3Y41 phosphorylation. Instead, chromatin immunoprecipitation experiment shows that Oncogenic Y505FLck kinase binds to the Lmo2 promoter in vivo. This result raises the possibility that Oncogenic Lck may activate Lmo2 promoter through direct interaction. The resulting increase in Lmo2 expression can potentially contribute to the transforming capacity of Oncogenic Lck. All together, we report here a novel mechanism of Lmo2 gene regulation by the Oncogenic Lck kinase. Previously, we have characterized the role of STAT5b in Lck-mediated transformation. The Lmo2 gene promoter lacks predicted STAT5 binding sites suggesting that Lck-mediated Lmo2 promoter activation is STAT5-independent. Our data suggest that Oncogenic Lck can initiate both STAT5- dependent and independent signals that are likely to be controlled by the spatial localization of the oncoprotein. Subcellular compartmentalization of Lck therefore adds to the complexity that defines cellular transformation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4008. doi:1538-7445.AM2012-4008
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nuclear localization of lymphocyte specific protein tyrosine kinase lck and its role in regulating lim domain only 2 lmo2 gene
Biochemical and Biophysical Research Communications, 2012Co-Authors: Srividya Venkitachalam, Fuyu Chueh, Chaolan YuAbstract:LIM domain only protein 2 (Lmo2) is a transcription factor that plays a critical role in the development of T-acute lymphoblastic leukemia (T-ALL). A previous report established a link between Lmo2 expression and the nuclear presence of Oncogenic Janus kinase 2 (JAK2), a non-receptor protein tyrosine kinase. The Oncogenic JAK2 kinase phosphorylates histone H3 on Tyr 41 that leads to the relief of Lmo2 promoter repression and subsequent gene expression. Similar to JAK2, constitutive activation of lymphocyte-specific protein tyrosine kinase (Lck) has been implicated in lymphoid malignancies. However, it is not known whether Oncogenic Lck regulates Lmo2 expression through a similar mechanism. We show here that Lmo2 expression is significantly elevated in T cell leukemia LSTRA overexpressing active Lck kinase and in HEK 293 cells expressing Oncogenic Y505FLck kinase. Nuclear localization of active Lck kinase was confirmed in both Lck-transformed cells by subcellular fractionation and immunofluorescence microscopy. More importantly, in contrast to Oncogenic JAK2, Oncogenic Lck kinase does not result in significant increase in histone H3 phosphorylation on Tyr 41. Instead, chromatin immunoprecipitation experiment shows that Oncogenic Y505FLck kinase binds to the Lmo2 promoter in vivo. This result raises the possibility that Oncogenic Lck may activate Lmo2 promoter through direct interaction.
Srividya Venkitachalam - One of the best experts on this subject based on the ideXlab platform.
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abstract 4008 nuclear localization of lymphocyte specific protein tyrosine kinase lck and its role in regulating lim domain only 2 lmo2 gene
Cancer Research, 2012Co-Authors: Srividya Venkitachalam, Fuyu ChuehAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Lmo2 is a transcription factor that plays a critical role in both hematopoietic development and vascular remodeling. Lmo2 - associated chromosomal translocations are believed to play a major role in the development of T-cell acute lymphoblastic leukemia (T-ALL). Lmo2 is also shown to interact with the T-cell acute lymphocytic leukemia protein (TAL1) in leukemia. A previous report established a link between Lmo2 expression and the unexpected nuclear presence of Oncogenic Janus kinase 2 (JAK2), a non-receptor protein tyrosine kinase. However, it is not known whether other Oncogenic tyrosine kinases regulate Lmo2 expression through a similar mechanism. We showed previously that Oncogenic Lck kinase promotes cellular transformation through the activation of signal transducer and activator of transcription 5b (Mol Cancer Res 4:39). In this report, we describe novel nuclear localization of Lck and its role in regulating Lmo2 expression. Lck, like most Src family kinases, is primarily known as a cytosolic or membrane-associated kinase. Using subcellular fractionation and immunofluorescence microscopy, we identified nuclear localization of Lck in murine leukemia cells (LSTRA) that overexpress Lck kinase. Nuclear Lck was also detected in 293 cells expressing constitutively active Y505FLck. Additionally, phosphorylation of the positive-regulatory tyrosine 394 confirmed the active status of nuclear Lck. These data suggest that Oncogenic Lck may have an uncharacterized function within the nucleus that supports cellular transformation. Lmo2 expression was significantly elevated both in LSTRA leukemia and in 293 cells expressing Oncogenic Y505FLck kinase. The Oncogenic JAK2 kinase phosphorylates histone H3 on Y41 that leads to the relief of Lmo2 promoter repression and subsequent gene expression. However, expression of Oncogenic Lck kinase does not result in significant increase in H3Y41 phosphorylation. Instead, chromatin immunoprecipitation experiment shows that Oncogenic Y505FLck kinase binds to the Lmo2 promoter in vivo. This result raises the possibility that Oncogenic Lck may activate Lmo2 promoter through direct interaction. The resulting increase in Lmo2 expression can potentially contribute to the transforming capacity of Oncogenic Lck. All together, we report here a novel mechanism of Lmo2 gene regulation by the Oncogenic Lck kinase. Previously, we have characterized the role of STAT5b in Lck-mediated transformation. The Lmo2 gene promoter lacks predicted STAT5 binding sites suggesting that Lck-mediated Lmo2 promoter activation is STAT5-independent. Our data suggest that Oncogenic Lck can initiate both STAT5- dependent and independent signals that are likely to be controlled by the spatial localization of the oncoprotein. Subcellular compartmentalization of Lck therefore adds to the complexity that defines cellular transformation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4008. doi:1538-7445.AM2012-4008
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nuclear localization of lymphocyte specific protein tyrosine kinase lck and its role in regulating lim domain only 2 lmo2 gene
Biochemical and Biophysical Research Communications, 2012Co-Authors: Srividya Venkitachalam, Fuyu Chueh, Chaolan YuAbstract:LIM domain only protein 2 (Lmo2) is a transcription factor that plays a critical role in the development of T-acute lymphoblastic leukemia (T-ALL). A previous report established a link between Lmo2 expression and the nuclear presence of Oncogenic Janus kinase 2 (JAK2), a non-receptor protein tyrosine kinase. The Oncogenic JAK2 kinase phosphorylates histone H3 on Tyr 41 that leads to the relief of Lmo2 promoter repression and subsequent gene expression. Similar to JAK2, constitutive activation of lymphocyte-specific protein tyrosine kinase (Lck) has been implicated in lymphoid malignancies. However, it is not known whether Oncogenic Lck regulates Lmo2 expression through a similar mechanism. We show here that Lmo2 expression is significantly elevated in T cell leukemia LSTRA overexpressing active Lck kinase and in HEK 293 cells expressing Oncogenic Y505FLck kinase. Nuclear localization of active Lck kinase was confirmed in both Lck-transformed cells by subcellular fractionation and immunofluorescence microscopy. More importantly, in contrast to Oncogenic JAK2, Oncogenic Lck kinase does not result in significant increase in histone H3 phosphorylation on Tyr 41. Instead, chromatin immunoprecipitation experiment shows that Oncogenic Y505FLck kinase binds to the Lmo2 promoter in vivo. This result raises the possibility that Oncogenic Lck may activate Lmo2 promoter through direct interaction.
Chaolan Yu - One of the best experts on this subject based on the ideXlab platform.
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nuclear localization of lymphocyte specific protein tyrosine kinase lck and its role in regulating lim domain only 2 lmo2 gene
Biochemical and Biophysical Research Communications, 2012Co-Authors: Srividya Venkitachalam, Fuyu Chueh, Chaolan YuAbstract:LIM domain only protein 2 (Lmo2) is a transcription factor that plays a critical role in the development of T-acute lymphoblastic leukemia (T-ALL). A previous report established a link between Lmo2 expression and the nuclear presence of Oncogenic Janus kinase 2 (JAK2), a non-receptor protein tyrosine kinase. The Oncogenic JAK2 kinase phosphorylates histone H3 on Tyr 41 that leads to the relief of Lmo2 promoter repression and subsequent gene expression. Similar to JAK2, constitutive activation of lymphocyte-specific protein tyrosine kinase (Lck) has been implicated in lymphoid malignancies. However, it is not known whether Oncogenic Lck regulates Lmo2 expression through a similar mechanism. We show here that Lmo2 expression is significantly elevated in T cell leukemia LSTRA overexpressing active Lck kinase and in HEK 293 cells expressing Oncogenic Y505FLck kinase. Nuclear localization of active Lck kinase was confirmed in both Lck-transformed cells by subcellular fractionation and immunofluorescence microscopy. More importantly, in contrast to Oncogenic JAK2, Oncogenic Lck kinase does not result in significant increase in histone H3 phosphorylation on Tyr 41. Instead, chromatin immunoprecipitation experiment shows that Oncogenic Y505FLck kinase binds to the Lmo2 promoter in vivo. This result raises the possibility that Oncogenic Lck may activate Lmo2 promoter through direct interaction.
Chiswili Chabu - One of the best experts on this subject based on the ideXlab platform.
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egfr arf6 regulation of hh signalling stimulates Oncogenic ras tumour overgrowth
Nature Communications, 2017Co-Authors: Chiswili ChabuAbstract:Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How Oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with Oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring Oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in Oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog. EGFR signalling is required for Oncogenic Ras driven tumorigenesis. In this study, using aDrosophilatumour model the authors demonstrate that depletion of Arf6, a Ras-related GTP-binding protein activated by EGFR, supresses Oncogenic Ras driven overgrowth via modulation of Hedgehog signalling.
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Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth
Development (Cambridge England), 2014Co-Authors: Chiswili ChabuAbstract:Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how Oncogenic Ras exerts its effects. Furthermore, cancers with Oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of Oncogenic Ras in an in vivo Drosophila mosaic screen. We found that Oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses Oncogenic Ras-mediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during Oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches.
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Oncogenic Ras stimulates Eiger/TNF exocytosis to promote
2014Co-Authors: Chiswili ChabuAbstract:Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how Oncogenic Ras exerts its effects. Furthermore, cancers with Oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of Oncogenic Ras in an in vivo Drosophila mosaic screen. We found that Oncogenic Ras elevates exocytosis and promotesthe export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses Oncogenic Rasmediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during Oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches.
Tony Hunter - One of the best experts on this subject based on the ideXlab platform.
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Oncogenic kinase signalling
Nature, 2001Co-Authors: Peter Blumejensen, Tony HunterAbstract:Protein-tyrosine kinases (PTKs) are important regulators of intracellular signal-transduction pathways mediating development and multicellular communication in metazoans. Their activity is normally tightly controlled and regulated. Perturbation of PTK signalling by mutations and other genetic alterations results in deregulated kinase activity and malignant transformation. The lipid kinase phosphoinositide 3-OH kinase (PI(3)K) and some of its downstream targets, such as the protein-serine/threonine kinases Akt and p70 S6 kinase (p70S6K), are crucial effectors in Oncogenic PTK signalling. This review emphasizes how Oncogenic conversion of protein kinases results from perturbation of the normal autoinhibitory constraints on kinase activity and provides an update on our knowledge about the role of deregulated PI(3)K/Akt and mammalian target of rapamycin/p70S6K signalling in human malignancies.