title: Genetic characterization of p27(kip1) and stathmin in controlling cell proliferation in vivo.
abstract: The CDK inhibitor p27(kip1) is a critical regulator of cell cycle progression, but the mechanisms by which p27(kip1) controls cell proliferation in vivo are still not fully elucidated. We recently demonstrated that the microtubule destabilizing protein stathmin is a relevant p27(kip1) binding partner. To get more insights into the in vivo significance of this interaction, we generated p27(kip1) and stathmin double knock-out (DKO) mice. Interestingly, thorough characterization of DKO mice demonstrated that most of the phenotypes of p27(kip1) null mice linked to the hyper-proliferative behavior, such as the increased body and organ weight, the outgrowth of the retina basal layer and the development of pituitary adenomas, were reverted by co-ablation of stathmin. In vivo analyses showed a reduced proliferation rate in DKO compared to p27(kip1) null mice, linked, at molecular level, to decreased kinase activity of CDK4/6, rather than of CDK1 and CDK2. Gene expression profiling of mouse thymuses confirmed the phenotypes observed in vivo, showing that DKO clustered with WT more than with p27 knock-out tissue. Taken together, our results demonstrate that stathmin cooperates with p27(kip1) to control the early phase of G1 to S phase transition and that this function may be of particular relevance in the context of tumor progression.
authors.affiliation: a Department of Translational Research; Division of Experimental Oncology 2; CRO of Aviano, National Cancer Institute ; Aviano , Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pellizzari
authors.forename: Linda
authors.initials: L
authors.lastname: Fabris
authors.forename: Sara
authors.initials: S
authors.lastname: D'Andrea
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Canzonieri
authors.forename: Daniela
authors.initials: D
authors.lastname: Marconi
authors.forename: Monica
authors.initials: M
authors.lastname: Schiappacassi
authors.forename: Sara
authors.initials: S
authors.lastname: Benevol
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics*; D005260:Female; D016193:G1 Phase; D020869:Gene Expression Profiling; D005877:Gigantism / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D016196:S Phase; D050777:Stathmin / Q000172:deficiency / Q000235:genetics*; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
chemical_list: D050777:Stathmin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: BrdU, 5-bromo-2-deoxyuridine; CDK, cyclin-dependent kinase; DKO, double knock-out; JAK-STAT, janus kinase/signal transducers and activators of transcription; KO, knock-out; MAPK, mitogen-activated protein kinase; Stm, stathmin; WT, wild type; cell cycle; gene knock-out; p27kip1; proliferation; signaling pathway; stathmin