title: G1/S phase progression is regulated by PLK1 degradation through the CDK1/βTrCP axis.
abstract: Polo-like kinase 1 (PLK1) is a serine/threonine kinase involved in several stages of the cell cycle, including the entry and exit from mitosis, and cytokinesis. Furthermore, it has an essential role in the regulation of DNA replication. Together with cyclin A, PLK1 also promotes CDH1 phosphorylation to trigger its ubiquitination and degradation, allowing cell cycle progression. The PLK1 levels in different type of tumors are very high compared to normal tissues, which is consistent with its role in promoting proliferation. Therefore, several PLK1 inhibitors have been developed and tested for the treatment of cancer. Here, we further analyzed PLK1 degradation and found that cytoplasmic PLK1 is ubiquitinated and subsequently degraded by the SCFβTrCP/proteasome. This procedure is triggered when heat shock protein (HSP) 90 is inhibited with geldanamycin, which results in misfolding of PLK1. We also identified CDK1 as the major kinase involved in this degradation. Our work shows for the first time that HSP90 inhibition arrests cell cycle progression at the G1/S transition. This novel mechanism inhibits CDH1 degradation through CDK1-dependent PLK1 destruction by the SCFβTrCP/proteasome. In these conditions, CDH1 substrates do not accumulate and cell cycle arrests, providing a novel pathway for regulation of the cell cycle at the G1-to-S boundary.-Giráldez, S., Galindo-Moreno, M., Limón-Mortés, M. C., Rivas, A. C., Herrero-Ruiz, J., Mora-Santos, M., Sáez, C., Japón, M. Á., Tortolero, M., Romero, F. G1/S phase progression is regulated by PLK1 degradation through the CDK1/βTrCP axis.
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: Servando
authors.initials: S
authors.lastname: Giráldez
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galindo-Moreno
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Limón-Mortés
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rivas
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Herrero-Ruiz
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Mora-Santos
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, Seville, Spain.|Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sáez
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, Seville, Spain.|Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Miguel Á
authors.initials: MÁ
authors.lastname: Japón
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Tortolero
authors.affiliation: Departamento de Microbiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain; frport@us.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Romero
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D010957:Plasmids; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D000097869:Polo-Like Kinase 1
keywords: HSP90; cell cycle; protein degradation; ubiquitin ligase