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Richard K. Assoian - One of the best experts on this subject based on the ideXlab platform.
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joint requirement for rac and erk activities underlies the mid G1 Phase induction of cyclin d1 and s Phase entry in both epithelial and mesenchymal cells
Journal of Biological Chemistry, 2008Co-Authors: Eric A Klein, Latoya E Campbell, Devashish Kothapalli, Alaina K Fournier, Richard K. AssoianAbstract:Cyclin D1 gene induction is a key event in G1 Phase progression. Our previous studies indicated that signaling to cyclin D1 is cell type-dependent because the timing of cyclin D1 gene expression in MCF10A mammary epithelial cells and mesenchymal cells such as fibroblasts and vascular smooth muscle cells is very different, with epithelial cells first expressing cyclin D1 in early rather than mid-G1 Phase. In this report, we induced a mesenchymal phenotype in MCF10A cells by long-term exposure to TGF-β and used the control and transitioned cells to examine cell type specificity of the signaling pathways that regulate cyclin D1 gene expression. We show that early-G1 Phase cyclin D1 gene expression in MCF10A cells is under the control of Rac, whereas mid-G1 Phase cyclin D1 induction requires parallel signaling from Rac and ERK, both in the control and transitioned cells. This combined requirement for Rac and ERK signaling is associated with an increased requirement for intracellular tension, Rb phosphorylation, and S Phase entry. A similar co-regulation of cyclin D1 mRNA by Rac and ERK is seen in primary mesenchymal cells. Overall, our results reveal two mechanistically distinct Phases of Rac-dependent cyclin D1 expression and emphasize that the acquisition of Rac/ERK co-dependence is required for the mid-G1 Phase induction of cyclin D1 associated with S Phase entry.
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phorbol ester induced G1 Phase arrest selectively mediated by protein kinase cδ dependent induction of p21
Journal of Biological Chemistry, 2005Co-Authors: Motonori Nakagawa, Richard K. Assoian, Devashish Kothapalli, Alaina K Fournier, Jose Luis Oliva, Marcelo G KazanietzAbstract:Abstract Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCδ mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 Phase impaired progression of lung adenocarcinoma cells into S Phase, an effect that was completely abolished by specific depletion of PKCδ, but not PKCα. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKCδ but not PKCα. Studies using luciferase reporters also revealed an essential role for PKCδ in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKCδ is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKCδ and G1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.
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phorbol ester induced G1 Phase arrest selectively mediated by protein kinase cδ dependent induction of p21
Journal of Biological Chemistry, 2005Co-Authors: Motonori Nakagawa, Richard K. Assoian, Devashish Kothapalli, Alaina K Fournier, Jose Luis Oliva, Marcelo G KazanietzAbstract:Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCδ mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 Phase impaired progression of lung adenocarcinoma cells into S Phase, an effect that was completely abolished by specific depletion of PKCδ, but not PKCα. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKCδ but not PKCα. Studies using luciferase reporters also revealed an essential role for PKCδ in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKCδ is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKCδ and G1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.
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Timing of cyclin D1 expression within G1 Phase is controlled by Rho
Nature Cell Biology, 2001Co-Authors: Catherine F. Welsh, Kristin Roovers, Jessie Villanueva, Martin A. Schwartz, Richard K. AssoianAbstract:The expression of cyclin D1 in mid-G1 Phase is associated with sustained ERK activity, and we show here that Rho is required for the sustained ERK signal. However, we also report that Rho inhibits an alternative Rac/Cdc42-dependent pathway, which results in a strikingly early G1-Phase expression of cyclin D1. Thus, cyclin D1 is induced in mid-G1 Phase because a Rho switch couples its expression to sustained ERK activity rather than Rac and Cdc42. Our results show that Rho is crucial for maintaining the correct timing of cyclin D1 expression in G1 Phase and describe a new role for cytoskeletal integrity in the regulation of cell cycle progression.
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Integrating the MAP kinase signal into the G1 Phase cell cycle machinery.
BioEssays : news and reviews in molecular cellular and developmental biology, 2000Co-Authors: Kristin Roovers, Richard K. AssoianAbstract:Growth factors and the extracellular matrix provide the environmental cues that control the proliferation of most cell types. The binding of growth factors and matrix proteins to receptor tyrosine kinases and integrins, respectively, regulates several cytoplasmic signal transduction cascades, among which activation of the mitogen-activated protein kinase cascade, ras --> Raf --> MEK --> ERK, is perhaps the best characterized. Curiously, ERK activation has been associated with both stimulation and inhibition of cell proliferation. In this review, we summarize recent studies that connect ERK signaling to G1 Phase cell cycle control and suggest that the cellular response to an ERK signal depends on both ERK signal intensity and duration. We also discuss studies showing that receptor tyrosine kinases and integrins differentially regulate the ERK signal in G1 Phase.
Ahmed Ghannam - One of the best experts on this subject based on the ideXlab platform.
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induction of G1 Phase cell cycle arrest and apoptosis pathway in mda mb 231 human breast cancer cells by sulfated polysaccharide extracted from laurencia papillosa
Cancer Cell International, 2016Co-Authors: Hossam Murad, Mohammad Hawat, Adnan Ekhtiar, Abdulmunim Aljapawe, Assef Abbas, Hussein Darwish, Oula Sbenati, Ahmed GhannamAbstract:Marine algae consumption is linked to law cancer incidences in countries that traditionally consume marine products. Hence, Phytochemicals are considered as potential chemo-preventive and chemotherapeutic agents against cancer. We investigated the effects of the algal sulfated polysaccharide extract (ASPE) from the red marine alga L. papillosa on MDA-MB-231 human breast cancer cell line. Flow cytometry analysis was performed to study the cell viability, cell cycle arrest and apoptosis. Changes in the expression of certain genes associated with cell cycle regulation was conducted by PCR real time analyses. Further investigations on apoptotic molecules was performed by ROS measurement and protein profiling. ASPE at low doses (10 µg/ml), inhibited cell proliferation, and arrested proliferating MDA-MB-231 cells at G1-Phase. However, higher doses (50 µg/ml), triggered apoptosis in those cells. The low dose of ASPE also caused up-regulation of Cip1/p21 and Kip1/p27 and down-regulation of cyclins D1, D2, and E1 transcripts and their related cyclin dependent kinases: Cdk2, Cdk4, and Cdk6. The higher doses of ASPE initiated a dose-dependent apoptotic death in MDA-MB-231 by induction of Bax transcripts, inhibition of Bcl-2 and cleavage of Caspase-3 protein. Over-generation of reactive oxygen species (ROS) were also observed in MDA-MB-231 treated cells. These findings indicated that ASPE induces G1-Phase arrest and apoptosis in MDA-MB-231 cells. ASPE may serve as a potential therapeutic agent for breast cancer.
Katie M Reindl - One of the best experts on this subject based on the ideXlab platform.
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enterolactone induces G1 Phase cell cycle arrest in nonsmall cell lung cancer cells by downregulating cyclins and cyclin dependent kinases
Nutrition and Cancer, 2017Co-Authors: Shireen Chikara, Kaitlin Lindsey, Harsharan Dhillon, Sujan Mamidi, Jeffrey D Kittilson, Melpo Christofidousolomidou, Katie M ReindlAbstract:ABSTRACTFlaxseed is a rich source of the plant lignan secoisolariciresinol diglucoside (SDG), which is metabolized into mammalian lignans enterodiol (ED) and enterolactone (EL) in the digestive tract. The anticancer properties of these lignans have been demonstrated for various cancer types, but have not been studied for lung cancer. In this study, we investigated the anticancer effects of EL for several nonsmall cell lung cancer (NSCLC) cell lines of various genetic backgrounds. EL inhibited the growth of A549, H441, and H520 lung cancer cells in concentration- and time-dependent manners. The antiproliferative effects of EL for lung cancer cells were not due to enhanced cell death, but rather due to G1-Phase cell cycle arrest. Molecular studies revealed that EL decreased mRNA or protein expression levels of the G1-Phase promoters cyclin D1, cyclin E, cyclin-dependent kinases (CDK)-2, -4, and -6, and p-cdc25A; decreased phosphorylated retinoblastoma (p-pRb) protein levels; and simultaneously increased lev...
Marcelo G Kazanietz - One of the best experts on this subject based on the ideXlab platform.
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phorbol ester induced G1 Phase arrest selectively mediated by protein kinase cδ dependent induction of p21
Journal of Biological Chemistry, 2005Co-Authors: Motonori Nakagawa, Richard K. Assoian, Devashish Kothapalli, Alaina K Fournier, Jose Luis Oliva, Marcelo G KazanietzAbstract:Abstract Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCδ mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 Phase impaired progression of lung adenocarcinoma cells into S Phase, an effect that was completely abolished by specific depletion of PKCδ, but not PKCα. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKCδ but not PKCα. Studies using luciferase reporters also revealed an essential role for PKCδ in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKCδ is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKCδ and G1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.
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phorbol ester induced G1 Phase arrest selectively mediated by protein kinase cδ dependent induction of p21
Journal of Biological Chemistry, 2005Co-Authors: Motonori Nakagawa, Richard K. Assoian, Devashish Kothapalli, Alaina K Fournier, Jose Luis Oliva, Marcelo G KazanietzAbstract:Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCδ mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 Phase impaired progression of lung adenocarcinoma cells into S Phase, an effect that was completely abolished by specific depletion of PKCδ, but not PKCα. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKCδ but not PKCα. Studies using luciferase reporters also revealed an essential role for PKCδ in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKCδ is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKCδ and G1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.
Charles J. Sherr - One of the best experts on this subject based on the ideXlab platform.
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cyclic amp induced G1 Phase arrest mediated by an inhibitor p27kip1 of cyclin dependent kinase 4 activation
Cell, 1994Co-Authors: Junya Kato, Masaaki Matsuoka, Kornelia Polyak, Joan Massague, Charles J. SherrAbstract:Abstract Cyclic AMP (cAMP) blocks the mitogenic effects of colony-stimulating factor 1 (CSF-1) in macrophages, inducing cell cycle arrest in mid-G1 Phase. Complexes between cyclin D1 and cyclin-dependent kinase 4 (cdk4) assemble in growth arrested cells, but cdk4 is not phosphorylated in vivo by the cdk-activating kinase (CAK) and remains inactive. Although undetectable in lysates of cAMP-treated cells, active CAK is recovered after antibody precipitation, indicating that it is not the direct target of inhibition. Levels of the cdk inhibitor p27 Kip1 increase in cAMP-treated cells, and its immunodepletion from inhibitory lysates restores CAK-mediated cdk4 activation. Kip1 does not bind to CAK, but its association with cyclin D-cdk4 prevents CAK from phosphorylating and activating the holoenzyme.
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overexpression of mouse d type cyclins accelerates G1 Phase in rodent fibroblasts
Genes & Development, 1993Co-Authors: Dawn E Quelle, Junya Kato, Martine F Roussel, R A Ashmun, Sheila A Shurtleff, Dafna Barsagi, Charles J. SherrAbstract:Mammalian D-type cyclins are growth factor-regulated, delayed early response genes that are presumed to control progression through the G1 Phase of the cell cycle by governing the activity of cyclin-dependent kinases (cdks). Overexpression of mouse cyclin D1 in serum-stimulated mouse NIH-3T3 and rat-2 fibroblasts increased their rates of G0 to S- and G1- to S-Phase transit by several hours, leading to an equivalent contraction of their mean cell generation times. Although such cells remained contact inhibited and anchorage dependent, they manifested a reduced serum requirement for growth and were smaller in size than their normal counterparts. Ectopic expression of cyclin D2 in rodent fibroblasts, either alone or together with exogenous cdk4, shortened their G0- to S-Phase interval and reduced their serum dependency, but cyclin D2 alone did not alter cell size significantly. When cells were microinjected during the G2 interval with a monoclonal antibody specifically reactive to cyclin D1, parental rodent fibroblasts and derivatives overexpressing this cyclin were inhibited from entering S Phase, but cells injected near the G1/S Phase transition were refractory to antibody-induced growth suppression. Thus, cyclin D1, and most likely D2, are rate limiting for G1progression.
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colony stimulating factor 1 regulates novel cyclins during the G1 Phase of the cell cycle
Cell, 1991Co-Authors: Hitoshl Matsushime, Charles J. Sherr, Martine F Roussel, Richard A AshmunAbstract:Three mouse cyclin-like (CYL) genes were isolated, two of which are regulated by colony-stimulating factor 1 (CSF-1) during the G1 Phase of the macrophage cell cycle. CSF-1 deprivation during G1 leads to rapid degradation of CYL proteins (p36CYL) and correlates with failure to initiate DNA synthesis. However, after entering S Phase, macrophages no longer require CSF-1 and can complete cell division without expressing CYL genes. During G1, p36CYL is phosphorylated and associates with a polypeptide antigenically related to p34cdc2. The timing of p36CYL expression, its rapid turnover in the absence of CSF-1, and its phosphorylation and transient binding to a cdc2-related polypeptide suggest that CYL genes may function during S Phase commitment.
