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Lin Zhang - One of the best experts on this subject based on the ideXlab platform.
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mical1 facilitates breast cancer cell proliferation via ros sensitive erk Cyclin D pathway
Journal of Cellular and Molecular Medicine, 2018Co-Authors: Wenjie Deng, Yueyuan Wang, Shuo Zhao, Yujie Zhang, Yan Chen, Xuyang Zhao, Lei Liu, Shixiu Sun, Lin ZhangAbstract:Molecule interacting with CasL 1 (MICAL1) is a multiDomain flavoprotein mono-oxygenase that strongly involves in cytoskeleton Dynamics anD cell oxiDoreDuction metabolism. Recently, results from our laboratory have shown that MICAL1 moDulates reactive oxygen species (ROS) proDuction, anD the latter then activates phosphatiDyl inositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performeD this stuDy to assess the involvement of MICAL1 in breast cancer cell proliferation anD to explore the potential molecular mechanism. We noticeD that Depletion of MICAL1 markeDly reDuceD cell proliferation in breast cancer cell line MCF-7 anD T47D. This effect of MICAL1 on proliferation was inDepenDent of wnt/β-catenin anD NF-κB pathways. Interestingly, Depletion of MICAL1 significantly inhibiteD ROS proDuction, DecreaseD p-ERK expression anD unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increaseD p-ERK level as well as p-ERK nucleus translocation. Moreover, we investigateD the effect of MICAL1 on cell cycle-relateD proteins. MICAL1 positively regulateD CDK4 anD Cyclin D expression, but not CDK2, CDK6, Cyclin A anD Cyclin E. In aDDition, more expression of CDK4 anD Cyclin D by MICAL1 overexpression was blockeD by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuateD the increase in the p-ERK level in MICAL1-overexpresseD breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining Cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells.
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MICAL1 facilitates breast cancer cell proliferation via ROS-sensitive ERK/Cyclin D pathway.
Journal of Cellular and Molecular Medicine, 2018Co-Authors: Wenjie Deng, Yueyuan Wang, Shuo Zhao, Yujie Zhang, Yan Chen, Xuyang Zhao, Lei Liu, Shixiu Sun, Lin ZhangAbstract:Molecule interacting with CasL 1 (MICAL1) is a multiDomain flavoprotein mono-oxygenase that strongly involves in cytoskeleton Dynamics anD cell oxiDoreDuction metabolism. Recently, results from our laboratory have shown that MICAL1 moDulates reactive oxygen species (ROS) proDuction, anD the latter then activates phosphatiDyl inositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performeD this stuDy to assess the involvement of MICAL1 in breast cancer cell proliferation anD to explore the potential molecular mechanism. We noticeD that Depletion of MICAL1 markeDly reDuceD cell proliferation in breast cancer cell line MCF-7 anD T47D. This effect of MICAL1 on proliferation was inDepenDent of wnt/β-catenin anD NF-κB pathways. Interestingly, Depletion of MICAL1 significantly inhibiteD ROS proDuction, DecreaseD p-ERK expression anD unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increaseD p-ERK level as well as p-ERK nucleus translocation. Moreover, we investigateD the effect of MICAL1 on cell cycle-relateD proteins. MICAL1 positively regulateD CDK4 anD Cyclin D expression, but not CDK2, CDK6, Cyclin A anD Cyclin E. In aDDition, more expression of CDK4 anD Cyclin D by MICAL1 overexpression was blockeD by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuateD the increase in the p-ERK level in MICAL1-overexpresseD breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining Cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells.
Wenjie Deng - One of the best experts on this subject based on the ideXlab platform.
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mical1 facilitates breast cancer cell proliferation via ros sensitive erk Cyclin D pathway
Journal of Cellular and Molecular Medicine, 2018Co-Authors: Wenjie Deng, Yueyuan Wang, Shuo Zhao, Yujie Zhang, Yan Chen, Xuyang Zhao, Lei Liu, Shixiu Sun, Lin ZhangAbstract:Molecule interacting with CasL 1 (MICAL1) is a multiDomain flavoprotein mono-oxygenase that strongly involves in cytoskeleton Dynamics anD cell oxiDoreDuction metabolism. Recently, results from our laboratory have shown that MICAL1 moDulates reactive oxygen species (ROS) proDuction, anD the latter then activates phosphatiDyl inositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performeD this stuDy to assess the involvement of MICAL1 in breast cancer cell proliferation anD to explore the potential molecular mechanism. We noticeD that Depletion of MICAL1 markeDly reDuceD cell proliferation in breast cancer cell line MCF-7 anD T47D. This effect of MICAL1 on proliferation was inDepenDent of wnt/β-catenin anD NF-κB pathways. Interestingly, Depletion of MICAL1 significantly inhibiteD ROS proDuction, DecreaseD p-ERK expression anD unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increaseD p-ERK level as well as p-ERK nucleus translocation. Moreover, we investigateD the effect of MICAL1 on cell cycle-relateD proteins. MICAL1 positively regulateD CDK4 anD Cyclin D expression, but not CDK2, CDK6, Cyclin A anD Cyclin E. In aDDition, more expression of CDK4 anD Cyclin D by MICAL1 overexpression was blockeD by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuateD the increase in the p-ERK level in MICAL1-overexpresseD breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining Cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells.
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MICAL1 facilitates breast cancer cell proliferation via ROS-sensitive ERK/Cyclin D pathway.
Journal of Cellular and Molecular Medicine, 2018Co-Authors: Wenjie Deng, Yueyuan Wang, Shuo Zhao, Yujie Zhang, Yan Chen, Xuyang Zhao, Lei Liu, Shixiu Sun, Lin ZhangAbstract:Molecule interacting with CasL 1 (MICAL1) is a multiDomain flavoprotein mono-oxygenase that strongly involves in cytoskeleton Dynamics anD cell oxiDoreDuction metabolism. Recently, results from our laboratory have shown that MICAL1 moDulates reactive oxygen species (ROS) proDuction, anD the latter then activates phosphatiDyl inositol 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway which regulates breast cancer cell invasion. Herein, we performeD this stuDy to assess the involvement of MICAL1 in breast cancer cell proliferation anD to explore the potential molecular mechanism. We noticeD that Depletion of MICAL1 markeDly reDuceD cell proliferation in breast cancer cell line MCF-7 anD T47D. This effect of MICAL1 on proliferation was inDepenDent of wnt/β-catenin anD NF-κB pathways. Interestingly, Depletion of MICAL1 significantly inhibiteD ROS proDuction, DecreaseD p-ERK expression anD unfavourable for proliferative phenotype of breast cancer cells. Likewise, MICAL1 overexpression increaseD p-ERK level as well as p-ERK nucleus translocation. Moreover, we investigateD the effect of MICAL1 on cell cycle-relateD proteins. MICAL1 positively regulateD CDK4 anD Cyclin D expression, but not CDK2, CDK6, Cyclin A anD Cyclin E. In aDDition, more expression of CDK4 anD Cyclin D by MICAL1 overexpression was blockeD by PI3K/Akt inhibitor LY294002. LY294002 treatment also attenuateD the increase in the p-ERK level in MICAL1-overexpresseD breast cancer cells. Together, our results suggest that MICAL1 exhibits its effect on proliferation via maintaining Cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells.
Andrew B. Lassar - One of the best experts on this subject based on the ideXlab platform.
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Cyclin D–cDk4 activity moDulates the subnuclear localization anD interaction of MEF2 with SRC-family coactivators During skeletal muscle Differentiation
Genes & Development, 2002Co-Authors: Jean-bernard Lazaro, Peter Bailey, Andrew B. LassarAbstract:Prior work has inDicateD that D-type Cyclin–cDk4 complexes, which are only active in proliferating cells, can suppress the skeletal muscle Differentiation program in proliferating myoblasts. In this stuDy, we show that Cyclin D–cDk activity can block the activity of the MEF2 family of transcriptional regulators, which are crucial regulators of skeletal muscle gene expression. We have founD that Cyclin D–cDk activity blocks the association of MEF2C with the coactivator protein GRIP-1 anD thereby inhibits the activity of MEF2. During skeletal muscle Differentiation, GRIP-1 is localizeD to punctate nuclear structures anD can apparently tether MEF2 to such structures. Cotransfection of GRIP-1 can both potentiate the transcriptional activity of a Gal4–MEF2C construct anD inDuce MEF2C localization to punctate nuclear structures. Consistent with the absence of punctate nuclear GRIP-1 in proliferating myoblasts, we have founD that ectopic Cyclin D–cDk4 expression Disrupts the localization of both GRIP-1 anD MEF2C to these punctate subnuclear structures. Our finDings inDicate that Cyclin D–cDk4 activity represses skeletal muscle Differentiation in proliferating cells by blocking the association of MEF2 with the coactivator GRIP-1 anD concomitantly Disrupts the association of these factors with punctate nuclear subDomains within the cell.
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Cyclin D cDk4 activity moDulates the subnuclear localization anD interaction of mef2 with src family coactivators During skeletal muscle Differentiation
Genes & Development, 2002Co-Authors: Jean-bernard Lazaro, Peter Bailey, Andrew B. LassarAbstract:Prior work has inDicateD that D-type Cyclin–cDk4 complexes, which are only active in proliferating cells, can suppress the skeletal muscle Differentiation program in proliferating myoblasts. In this stuDy, we show that Cyclin D–cDk activity can block the activity of the MEF2 family of transcriptional regulators, which are crucial regulators of skeletal muscle gene expression. We have founD that Cyclin D–cDk activity blocks the association of MEF2C with the coactivator protein GRIP-1 anD thereby inhibits the activity of MEF2. During skeletal muscle Differentiation, GRIP-1 is localizeD to punctate nuclear structures anD can apparently tether MEF2 to such structures. Cotransfection of GRIP-1 can both potentiate the transcriptional activity of a Gal4–MEF2C construct anD inDuce MEF2C localization to punctate nuclear structures. Consistent with the absence of punctate nuclear GRIP-1 in proliferating myoblasts, we have founD that ectopic Cyclin D–cDk4 expression Disrupts the localization of both GRIP-1 anD MEF2C to these punctate subnuclear structures. Our finDings inDicate that Cyclin D–cDk4 activity represses skeletal muscle Differentiation in proliferating cells by blocking the association of MEF2 with the coactivator GRIP-1 anD concomitantly Disrupts the association of these factors with punctate nuclear subDomains within the cell.
Robert L. Sutherland - One of the best experts on this subject based on the ideXlab platform.
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Cyclin D as a therapeutic target in cancer
Nature Reviews Cancer, 2011Co-Authors: E A Musgrove, C. Elizabeth Caldon, Jane Barraclough, Andrew Stone, Robert L. SutherlandAbstract:Cyclin D1, anD to a lesser extent the other D-type Cyclins, is frequently DeregulateD in cancer anD is a biomarker of cancer phenotype anD Disease progression. The ability of these Cyclins to activate the Cyclin-DepenDent kinases (CDKs) CDK4 anD CDK6 is the most extensively DocumenteD mechanism for their oncogenic actions anD proviDes an attractive therapeutic target. Is this an effective means of targeting the Cyclin D oncogenes, anD how might the patient subgroups that are most likely to benefit be iDentifieD? Cyclin D–Cyclin-DepenDent kinase 4 (CDK4) or CDK6 activation promotes cell cycle progression through the phosphorylation of substrates, incluDing RB anD transcription factors with roles in proliferation anD Differentiation. These kinase complexes also target substrates with roles in centrosome Duplication, mitochonDrial function, cell growth, cell aDhesion anD motility, anD cytoskeletal moDelling. D-type Cyclins have non-catalytic roles in which interactions with chromatin-moDifying enzymes anD Diverse transcription factors, incluDing steroiD hormone receptors, leaDs to the transcriptional regulation of suites of genes that are involveD in proliferation anD Differentiation. InDepenDently of CDK activation, the D-type Cyclins also facilitate efficient DNA repair anD inDirectly activate CDK2 through the sequestration of CDK inhibitors. CCND1 is an establisheD human oncogene that is commonly overexpresseD through copy number alterations, or more rarely by mutation, or as a consequence of the Deregulation of mitogenic signalling Downstream of oncogenes such as ERBB2. CCND1 overexpression causes a number of potentially oncogenic responses in experimental moDels anD is associateD with poor patient outcome. Cyclin D1 anD its associateD CDKs are potential therapeutic targets. Promising results from early CDK inhibitors in experimental systems were not followeD by eviDence for efficacy in clinical trials. Possible reasons for this Disappointing outcome incluDe poor pharmacokinetics, suboptimal Dosing scheDules anD clinical testing in unselecteD patient populations. SeconD-generation, more selective inhibitors of CDK4 anD CDK6 are now unDergoing clinical testing. Possible alternative approaches to targeting Cyclin D1 incluDe the use of compounDs that affect CCND1 transcription or Cyclin D1 protein turnover, anD the use of combination therapies that simultaneously target multiple enD points of Cyclin D1 action. Central to the effective use of these novel approaches is the better selection of patient subgroups that are likely to responD. Is the ability of D-type Cyclins to activate Cyclin-DepenDent kinases an effective means of targeting these oncogenes, anD how might the patient subgroups that are most likely to benefit be iDentifieD?
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Cyclin D as a therapeutic target in cancer
Nature Reviews Cancer, 2011Co-Authors: E A Musgrove, C. Elizabeth Caldon, Jane Barraclough, Andrew Stone, Robert L. SutherlandAbstract:Cyclin D1, anD to a lesser extent the other D-type Cyclins, is frequently DeregulateD in cancer anD is a biomarker of cancer phenotype anD Disease progression. The ability of these Cyclins to activate the Cyclin-DepenDent kinases (CDKs) CDK4 anD CDK6 is the most extensively DocumenteD mechanism for their oncogenic actions anD proviDes an attractive therapeutic target. Is this an effective means of targeting the Cyclin D oncogenes, anD how might the patient subgroups that are most likely to benefit be iDentifieD?
Edwin K. Jackson - One of the best experts on this subject based on the ideXlab platform.
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aDenosine attenuates human coronary artery smooth muscle cell proliferation by inhibiting multiple signaling pathways that converge on Cyclin D
Hypertension, 2015Co-Authors: Raghvendra K. Dubey, Jürgen Fingerle, Delbert G. Gillespie, Marinella Rosselli, Bruno Imthurn, Edwin K. JacksonAbstract:The goal of this stuDy was to Determine whether anD how aDenosine affects the proliferation of human coronary artery smooth muscle cells (HCASMCs). In HCASMCs, 2-chloroaDenosine (stable aDenosine analogue), but not N(6)-cyclopentylaDenosine, CGS21680, or N(6)-(3-ioDobenzyl)-aDenosine-5'-N-methyluronamiDe, inhibiteD HCASMC proliferation (A2B receptor profile). 2-ChloroaDenosine increaseD cAMP, reDuceD phosphorylation (activation) of ERK anD Akt (protein kinases known to increase Cyclin D expression anD activity, respectively), anD reDuceD levels of Cyclin D1 (Cyclin that promotes cell-cycle progression in G1). Moreover, 2-chloroaDenosine inhibiteD expression of S-phase kinase-associateD protein-2 (Skp2; promotes proteolysis of p27(Kip1)) anD upregulateD levels of p27(Kip1) (cell-cycle regulator that impairs Cyclin D function). 2-ChloroaDenosine also inhibiteD signaling Downstream of Cyclin D, incluDing hyperphosphorylation of retinoblastoma protein anD expression of Cyclin A (S phase Cyclin). KnockDown of A2B receptors preventeD the effects of 2-chloroaDenosine on ERK1/2, Akt, Skp2, p27(Kip1), Cyclin D1, Cyclin A, anD proliferation. Likewise, inhibition of aDenylyl cyclase anD protein kinase A abrogateD 2-chloroaDenosine's inhibitory effects on Skp2 anD stimulatory effects on p27(Kip1) anD rescueD HCASMCs from 2-chloroaDenosine-meDiateD inhibition. KnockDown of p27(Kip1) also reverseD the inhibitory effects of 2-chloroaDenosine on HCASMC proliferation. In vivo, peri-arterial (rat carotiD artery) 2-chloroaDenosine (20 μmol/L for 7 Days) DownregulateD vascular expression of Skp2, upregulateD vascular expression of p27(Kip1), anD reDuceD neointima hyperplasia by 71% (P<0.05; neointimal thickness: control, 37 424±18 371 pixels; treateD, 10 352±2824 pixels). In conclusion, the aDenosine/A2B receptor/cAMP/protein kinase A axis inhibits HCASMC proliferation by blocking multiple signaling pathways (ERK1/2, Akt, anD Skp2) that converge at Cyclin D, a key G1 Cyclin that controls cell-cycle progression.
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ADenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D
Hypertension, 2015Co-Authors: Raghvendra K. Dubey, Jürgen Fingerle, Delbert G. Gillespie, Marinella Rosselli, Bruno Imthurn, Edwin K. JacksonAbstract:The goal of this stuDy was to Determine whether anD how aDenosine affects the proliferation of human coronary artery smooth muscle cells (HCASMCs). In HCASMCs, 2-chloroaDenosine (stable aDenosine analogue), but not N(6)-cyclopentylaDenosine, CGS21680, or N(6)-(3-ioDobenzyl)-aDenosine-5'-N-methyluronamiDe, inhibiteD HCASMC proliferation (A2B receptor profile). 2-ChloroaDenosine increaseD cAMP, reDuceD phosphorylation (activation) of ERK anD Akt (protein kinases known to increase Cyclin D expression anD activity, respectively), anD reDuceD levels of Cyclin D1 (Cyclin that promotes cell-cycle progression in G1). Moreover, 2-chloroaDenosine inhibiteD expression of S-phase kinase-associateD protein-2 (Skp2; promotes proteolysis of p27(Kip1)) anD upregulateD levels of p27(Kip1) (cell-cycle regulator that impairs Cyclin D function). 2-ChloroaDenosine also inhibiteD signaling Downstream of Cyclin D, incluDing hyperphosphorylation of retinoblastoma protein anD expression of Cyclin A (S phase Cyclin). KnockDown of A2B receptors preventeD the effects of 2-chloroaDenosine on ERK1/2, Akt, Skp2, p27(Kip1), Cyclin D1, Cyclin A, anD proliferation. Likewise, inhibition of aDenylyl cyclase anD protein kinase A abrogateD 2-chloroaDenosine's inhibitory effects on Skp2 anD stimulatory effects on p27(Kip1) anD rescueD HCASMCs from 2-chloroaDenosine-meDiateD inhibition. KnockDown of p27(Kip1) also reverseD the inhibitory effects of 2-chloroaDenosine on HCASMC proliferation. In vivo, peri-arterial (rat carotiD artery) 2-chloroaDenosine (20 μmol/L for 7 Days) DownregulateD vascular expression of Skp2, upregulateD vascular expression of p27(Kip1), anD reDuceD neointima hyperplasia by 71% (P
