title: SUMOylation regulates p27Kip1 stability and localization in response to TGFβ.
abstract: Exposure of normal and tumor-derived cells to TGFβ results in different outcomes, depending on the regulation of key targets. The CDK inhibitor p27(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle arrest. TGFβ treatment inhibits p27(Kip1) degradation and induces its nuclear translocation, through mechanisms that are still unknown. Recent evidences suggest that SUMOylation, a post-translational modification able to modulate the stability and subcellular localization of target proteins, critically modifies members of the TGFβ signaling pathway. Here, we demonstrate that p27(Kip1) is SUMOylated in response to TGFβ treatment. Using different p27(Kip1) point mutants, we identified lysine 134 (K134) as the residue modified by small ubiquitin-like modifier 1 (SUMO1) in response to TGFβ treatment. TGFβ-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27(Kip1). We observed that SUMOylation regulated p27(Kip1) binding to CDK2, thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187. Importantly, p27(Kip1) SUMOylation was necessary for proper cell cycle exit following TGFβ treatment. These data indicate that SUMOylation is a novel regulatory mechanism that modulates p27(Kip1) function in response to TGFβ stimulation. Given the involvement of TGFβ signaling in cancer cell proliferation and invasion, our data may shed light on an important aspect of this pathway during tumor progression.
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lovisa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology at the IFOM-IEO Campus, Milan 20139, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Citro
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Sonego
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dall'Acqua
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ranzuglia
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy Department of Scienze e Tecnologie Biomediche, MATI Center of Excellence, University of Udine, Udine 33010, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology at the IFOM-IEO Campus, Milan 20139, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Chiocca
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy gbaldassarre@cro.it mschiappacassi@cro.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Schiappacassi
authors.affiliation: Division of Experimental Oncology 2 Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy gbaldassarre@cro.it mschiappacassi@cro.it.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
mesh_terms: D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D058207:Sumoylation / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta
chemical_list: D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: SUMOylation; TGFβ; p27kip1