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G 1 /S phase progression is regulated by PLK1 degradation through the CDK1/βTrCP axis
Author(s) -
Giráldez Servando,
GalindoMoreno María,
LimónMortés M. Cristina,
Rivas A. Cristina,
HerreroRuiz Joaquín,
MoraSantos Mar,
Sáez Carmen,
Japón Miguel Á.,
Tortolero Maria,
Romero Francisco
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201601108r
Subject(s) - cyclin dependent kinase 1 , plk1 , cytokinesis , cyclin b1 , polo like kinase , microbiology and biotechnology , cell cycle , wee1 , proteasome , mitosis , ubiquitin , kinase , lactacystin , biology , chemistry , biochemistry , cell , proteasome inhibitor , cell division , gene
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 SCF βTrCP /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 G 1 /S transition. This novel mechanism inhibits CDH1 degradation through CDK1‐dependent PLK1 destruction by the SCF βTrCP /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 G 1 ‐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. G 1 /S phase progression is regulated by PLK1 degradation through the CDK1/βTrCP axis. FASEB J. 31, 2925–2936 (2017). www.fasebj.org