title: p27kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability.
abstract: The cyclin-dependent kinase (CDK) inhibitor p27(kip1) is a critical regulator of the G1/S-phase transition of the cell cycle and also regulates microtubule (MT) stability. This latter function is exerted by modulating the activity of stathmin, an MT-destabilizing protein, and by direct binding to MTs. We recently demonstrated that increased proliferation in p27(kip1)-null mice is reverted by concomitant deletion of stathmin in p27(kip1)/stathmin double-KO mice, suggesting that a CDK-independent function of p27(kip1) contributes to the control of cell proliferation. Whether the regulation of MT stability by p27(kip1) impinges on signaling pathway activation and contributes to the decision to enter the cell cycle is largely unknown. Here, we report that faster cell cycle entry of p27(kip1)-null cells was impaired by the concomitant deletion of stathmin. Using gene expression profiling coupled with bioinformatic analyses, we show that p27(kip1) and stathmin conjunctly control activation of the MAPK pathway. From a molecular point of view, we observed that p27(kip1), by controlling MT stability, impinges on H-Ras trafficking and ubiquitination levels, eventually restraining its full activation. Our study identifies a regulatory axis controlling the G1/S-phase transition, relying on the regulation of MT stability by p27(kip1) and finely controlling the spatiotemporal activation of the Ras-MAPK signaling pathway.
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Linda
authors.initials: L
authors.lastname: Fabris
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pellizzari
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: D'Andrea
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Joshua
authors.initials: J
authors.lastname: Armenia
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Schiappacassi
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016;
authors.forename: Mark R
authors.initials: MR
authors.lastname: Philips
authors.affiliation: Division of Pathology, II University of Rome "La Sapienza," Santo Andrea Hospital, 00100 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy; bbelletti@cro.it gbaldassarre@cro.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy; bbelletti@cro.it gbaldassarre@cro.it.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
mesh_terms: D000818:Animals; D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D050777:Stathmin / Q000378:metabolism
chemical_list: D050777:Stathmin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Ras; cell cycle; microtubules; p27kip1; stathmin