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: Stefania Berton, Ilenia Pellizzari, Linda Fabris, Sara D'Andrea, Ilenia Segatto, Vincenzo Canzonieri, Daniela Marconi, Monica Schiappacassi, Sara Benevol, Valter Gattei, Alfonso Colombatti, Barbara Belletti, Gustavo Baldassarre
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 13 Issue 19 Pg. 3100-11 ( 2014) ISSN: 1551-4005 [Electronic] United States
• PMID: 25486569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Stathmin
• Cyclin-Dependent Kinase Inhibitor p27
• CDC2 Protein Kinase
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• CDC2 Protein Kinase (genetics, metabolism)
• Cell Proliferation
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase 4 (genetics, metabolism)
• Cyclin-Dependent Kinase 6 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (deficiency, genetics)
• Female
• G1 Phase
• Gene Expression Profiling
• Gigantism (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Pituitary Gland (metabolism, pathology)
• S Phase
• Stathmin (deficiency, genetics)
• Thymus Gland (metabolism, pathology)