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Your search keyword '"Manenti, Stéphane"' showing total 7 results
Start Over Author "Manenti, Stéphane" Topic cell proliferation
7 results on '"Manenti, Stéphane"'

1. CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia.

Author

Bertoli S, Boutzen H, David L, Larrue C, Vergez F, Fernandez-Vidal A, Yuan L, Hospital MA, Tamburini J, Demur C, Delabesse E, Saland E, Sarry JE, Galcera MO, Mansat-De Mas V, Didier C, Dozier C, Récher C, and Manenti S

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Benzothiazoles pharmacology, Benzoxazoles pharmacology, Cell Cycle Checkpoints, Cell Death, Child, Coculture Techniques, Enzyme Inhibitors pharmacology, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HL-60 Cells, Humans, K562 Cells, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, RNA Interference, RNA, Messenger genetics, RNA, Messenger metabolism, STAT5 Transcription Factor metabolism, Signal Transduction, Tandem Repeat Sequences, Time Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured, cdc25 Phosphatases antagonists & inhibitors, cdc25 Phosphatases genetics, fms-Like Tyrosine Kinase 3 genetics, Cell Differentiation drug effects, Cell Proliferation drug effects, Leukemia, Myeloid, Acute enzymology, cdc25 Phosphatases metabolism, fms-Like Tyrosine Kinase 3 metabolism
Abstract

We investigated cell cycle regulation in acute myeloid leukemia cells expressing the FLT3-ITD mutated tyrosine kinase receptor, an underexplored field in this disease. Upon FLT3 inhibition, CDC25A mRNA and protein were rapidly down-regulated, while levels of other cell cycle proteins remained unchanged. This regulation was dependent on STAT5, arguing for FLT3-ITD-dependent transcriptional regulation of CDC25A. CDC25 inhibitors triggered proliferation arrest and cell death of FLT3-ITD as well as FLT3-ITD/TKD AC-220 resistant cells, but not of FLT3-wt cells. Consistently, RNA interference-mediated knock-down of CDC25A reduced the proliferation of FLT3-ITD cell lines. Finally, the clonogenic capacity of primary FLT3-ITD AML cells was reduced by the CDC25 inhibitor IRC-083864, while FLT3-wt AML and normal CD34+ myeloid cells were unaffected. In good agreement, in a cohort of 100 samples from AML patients with intermediate-risk cytogenetics, high levels of CDC25A mRNA were predictive of higher clonogenic potential in FLT3-ITD+ samples, not in FLT3-wt ones.Importantly, pharmacological inhibition as well as RNA interference-mediated knock-down of CDC25A also induced monocytic differentiation of FLT3-ITD positive cells, as judged by cell surface markers expression, morphological modifications, and C/EBPα phosphorylation. CDC25 inhibition also re-induced monocytic differentiation in primary AML blasts carrying the FLT3-ITD mutation, but not in blasts expressing wild type FLT3. Altogether, these data identify CDC25A as an early cell cycle transducer of FLT3-ITD oncogenic signaling, and as a promising target to inhibit proliferation and re-induce differentiation of FLT3-ITD AML cells.

Published
2015
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2. Targeting CHK1 inhibits cell proliferation in FLT3-ITD positive acute myeloid leukemia.

Author

Yuan LL, Green A, David L, Dozier C, Récher C, Didier C, Tamburini J, and Manenti S

Subjects
Apoptosis drug effects, Base Sequence, Cell Cycle drug effects, Cell Line, Tumor, Checkpoint Kinase 1, DNA Primers, Humans, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute metabolism, Phosphorylation, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism, fms-Like Tyrosine Kinase 3 metabolism, Cell Proliferation, Leukemia, Myeloid, Acute pathology, Protein Kinases drug effects
Abstract

CHK1 Ser/Thr kinase, a well characterized regulator of DNA damage response, is also involved in normal cell cycle progression. In this study, we investigate how CHK1 participates to proliferation of acute myeloid leukemia cells expressing the mutated FLT3-ITD tyrosine kinase receptor. Pharmacological inhibition of CHK1 as well as its shRNA mediated down regulation reduced the proliferation rate of FLT-ITD expressing leukemic cell lines in a cytostatic manner. Flow cytometry analysis revealed no accumulation in a specific phase of the cell cycle upon CHK1 inhibition. Accordingly, lentiviral-mediated CHK1 overexpression increased the proliferation rate of FLT3-ITD expressing cells, as judged by cell viability and [3H] thymidine incorporation experiments. By contrast, expression of a ser280 mutant did not, suggesting that phosphorylation of this residue is an important determinant of CHK1 proliferative function. Clonogenic growth of primary leukemic cells from patients in semi-solid medium was reduced upon CHK1 inhibition, confirming the data obtained with leukemic established cell lines. Surprisingly, 3 out of 4 CHK1 inhibitory compounds tested in this study were also potent inhibitors of the FLT3-ITD tyrosine kinase receptor. Altogether, these data identify CHK1 as a regulator of FLT3-ITD-positive leukemic cells proliferation, and they open interesting perspectives in terms of new therapeutic strategies for these pathologies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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3. Polo-like kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells.

Author

Renner AG, Dos Santos C, Recher C, Bailly C, Créancier L, Kruczynski A, Payrastre B, and Manenti S

Subjects
Cell Cycle Proteins analysis, Gene Expression Regulation, Leukemic, Humans, Neoplasm Proteins, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases analysis, Proto-Oncogene Proteins analysis, Pteridines pharmacology, RNA, Small Interfering pharmacology, Tumor Cells, Cultured, Polo-Like Kinase 1, Cell Cycle Proteins antagonists & inhibitors, Cell Proliferation drug effects, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors
Abstract

Polo-like kinase 1 (Plk1) is a major mitotic regulator overexpressed in many solid tumors. Its role in hematopoietic malignancies is still poorly characterized. In this study, we demonstrate that Plk1 is highly expressed in leukemic cell lines, and overexpressed in a majority of samples from patients with acute myeloid leukemia compared with normal progenitors. A pharmacologic inhibitor, BI2536, blocks proliferation in established cell lines, and dramatically inhibits the clonogenic potential of leukemic cells from patients. Plk1 knockdown by small interfering RNA also blocked proliferation of leukemic cell lines and the clonogenic potential of primary cells from patients. Interestingly, normal primary hematopoietic progenitors are less sensitive to Plk1 inhibition than leukemic cells, whose proliferation is dramatically decreased by the inhibitor. These results highlight Plk1 as a potentially interesting therapeutic target for the treatment of acute myeloid leukemia.

Published
2009
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4. Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites

Author

Bosc, Claudie, Broin, Nicolas, Fanjul, Marjorie, Saland, Estelle, Farge, Thomas, Courdy, Charly, Batut, Aurélie, Masoud, Rawand, Larrue, Clément, Skuli, Sarah, Espagnolle, Nicolas, Pagès, Jean-Christophe, Carrier, Alice, Bost, Frédéric, Bertrand-Michel, Justine, Tamburini, Jérôme, Récher, Christian, Bertoli, Sarah, Mansat-De Mas, Véronique, Manenti, Stéphane, Sarry, Jean-Emmanuel, Joffre, Carine, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Métabolomique et Fluxomique (MetaToul) (TBI-MetaToul), MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), University of Geneva [Switzerland], Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellular and Molecular Physiopathology of Obesity and Diabetes [Nice], Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the ANR LABEX TOUCAN, the Cancéropole GSO, la Ligue régionale contre le Cancer, and la Ligue nationale contre le Cancer., ANR-11-IDEX-0002,UNITI,Université Fédérale de Toulouse(2011), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), University of Pennsylvania-University of Pennsylvania, Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Bodescot, Myriam, and Initiative d'excellence - Université Fédérale de Toulouse - - UNITI2011 - ANR-11-IDEX-0002 - IDEX - VALID

Subjects
Leukemia, Lipogenesis, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Endoplasmic Reticulum, Flow Cytometry, Lipid Metabolism, Article, Oxidative Phosphorylation, Mitochondria, Leukemia, Myeloid, Acute, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Autophagy, Leukaemia, Animals, Humans, lcsh:Q, lcsh:Science, Oxidation-Reduction, Cell Proliferation
Abstract

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria–endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia., How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML.

Published
2020
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5. STAT5-dependent regulation of CDC25A by miR-16 controls proliferation and differentiation in FLT3-ITD acute myeloid leukemia.

Author

Sueur, Gabrielle, Boutet, Alison, Gotanègre, Mathilde, Mansat-De Mas, Véronique, Besson, Arnaud, Manenti, Stéphane, and Bertoli, Sarah

Subjects
CELL proliferation, ACUTE myeloid leukemia, CELL differentiation, MESSENGER RNA, GENE expression
Abstract

We recently identified the CDC25A phosphatase as a key actor in proliferation and differentiation in acute myeloid leukemia expressing the FLT3-ITD mutation. In this paper we demonstrate that CDC25A level is controlled by a complex STAT5/miR-16 transcription and translation pathway working downstream of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR-16 restored CDC25A expression in response to FLT3-ITD inhibition. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]

Published
2020
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6. Translational Regulation by hnRNP H/F Is Essential for the Proliferation and Survival of Glioblastoma.

Author

Le Bras, Morgane, Gorelick, Noah, Pautet, Sylvain, Tyler, Betty, Manenti, Stéphane, Skuli, Nicolas, Millevoi, Stefania, and Cammas, Anne

Subjects
DISEASE progression, RNA-binding proteins, ANIMAL experimentation, GLIOMAS, CELL survival, CELLULAR signal transduction, CELL proliferation, TRANSFERASES, PHENOTYPES, DRUG resistance in cancer cells, MICE, PHOSPHORYLATION
Abstract

Simple Summary: Developing effective treatments for glioblastoma (GBM), a highly aggressive brain tumor that is resistant to current therapies, is an urgent medical need that can be addressed by the in-depth study of basic biology for the identification of relevant targets. The aim of the present study was to investigate the molecular mechanisms underlying the deregulation of protein synthesis associated with GBM progression and resistance to treatments. Our present work demonstrates the role of the RNA-binding proteins hnRNP H/F as key players in the control of protein synthesis in GBM through different overlapping mechanisms. Furthermore, our results show that hnRNP H/F potentiate cellular processes underlying the aggressive and resistant phenotype of GBMs, thus indicating hnRNP H/F as a potential target for therapeutic intervention. Deregulation of mRNA translation is a widespread characteristic of glioblastoma (GBM), aggressive malignant brain tumors that are resistant to conventional therapies. RNA-binding proteins (RBPs) play a critical role in translational regulation, yet the mechanisms and impact of these regulations on cancer development, progression and response to therapy remain to be fully understood. Here, we showed that hnRNP H/F RBPs are potent regulators of translation through several mechanisms that converge to modulate the expression and/or the activity of translation initiation factors. Among these, hnRNP H/F regulate the phosphorylation of eIF4E and its translational targets by controlling RNA splicing of the A-Raf kinase mRNA, which in turn modulates the MEK-ERK/MAPK signaling pathway. The underlying mechanism involves RNA G-quadruplex (RG4s), RNA structures whose modulation phenocopies hnRNP H/F translation regulation in GBM cells. Our results highlighted that hnRNP H/F are essential for key functional pathways regulating proliferation and survival of GBM, highlighting its targeting as a promising strategy for improving therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Published
2022
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7. p27Kip1 promotes invadopodia turnover and invasion through the regulation of the PAK1/Cortactin pathway.

Author

Jeannot, Pauline, Nowosad, Ada, Perchey, Renaud T., Callot, Caroline, Bennana, Evangeline, Katsube, Takanori, Mayeux, Patrick, Guillonneau, François, Manenti, Stéphane, and Besson, Arnaud

Subjects
*CYCLIN-dependent kinase inhibitors, *ONCOGENES, *CELL proliferation, *CORTACTIN, *METASTASIS
Abstract

p27Kip1 (p27) is a cyclin-CDK inhibitor and negative regulator of cell proliferation. p27 also controls other cellular processes including migration and cytoplasmic p27 can act as an oncogene. Furthermore, cytoplasmic p27 promotes invasion and metastasis, in part by promoting epithelial to mesenchymal transition. Herein, we find that p27 promotes cell invasion by binding to and regulating the activity of Cortactin, a critical regulator of invadopodia formation. p27 localizes to invadopodia and limits their number and activity. p27 promotes the interaction of Cortactin with PAK1. In turn, PAK1 promotes invadopodia turnover by phosphorylating Cortactin, and expression of Cortactin mutants for PAK-targeted sites abolishes p27's effect on invadopodia dynamics. Thus, in absence of p27, cells exhibit increased invadopodia stability due to impaired PAK1-Cortactin interaction, but their invasive capacity is reduced compared to wild-type cells. Overall, we find that p27 directly promotes cell invasion by facilitating invadopodia turnover via the Rac1/PAK1/ Cortactin pathway. [ABSTRACT FROM AUTHOR]

Published
2017
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