Role of p27Kip1 as a transcriptional regulator
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Oriol Bachs1, Edurne Gallastegui1, Serena Orlando1, Anna Bigas2, José Manuel Morante-Redolat3, Joan Serratosa4, Isabel Fariñas3, Rosa Aligué1 and Maria Jesús Pujol1
1Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, IDIBAPS, CIBERONC, Barcelona, Spain
2Program in Cancer Research, Institut Hospital Del Mar d'Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain
3Departamento de Biología Celular, Biología Funcional y Antropología Física and ERI de Biotecnología y Biomedicina, CIBERNED, Universidad de Valencia, Valencia, Spain
4Department of Cerebral Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Barcelona, Spain
Oriol Bachs, email: [email protected]
Keywords: p27Kip1; transcriptional regulation; cancer; neurodegeneration
Received: November 08, 2017 Accepted: May 01, 2018 Published: May 25, 2018
The protein p27Kip1 is a member of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors. It interacts with both the catalytic and the regulatory subunit (cyclin) and introduces a region into the catalytic cleave of the Cdk inducing its inactivation. Its inhibitory capacity can be modulated by specific tyrosine phosphorylations. p27Kip1 also behaves as a transcriptional regulator. It associates with specific chromatin domains through different transcription factors. ChIP on chip, ChIP-seq and expression microarray analysis allowed the identification of the transcriptional programs regulated by p27Kip1. Thus, important cellular functions as cell division cycle, respiration, RNA processing, translation and cell adhesion, are under p27Kip1 regulation. Moreover, genes involved in pathologies as cancer and neurodegeneration are also regulated by p27Kip1, suggesting its implication in these pathologies.
The carboxyl moiety of p27Kip1 can associate with different proteins, including transcriptional regulators. In contrast, its NH2-terminal region specifically interacts with cyclin-Cdk complexes. The general mechanistic model of how p27Kip1 regulates transcription is that it associates by its COOH region to the transcriptional regulators on the chromatin and by the NH2-domain to cyclin-Cdk complexes. After Cdk activation it would phosphorylate the specific targets on the chromatin leading to gene expression. This model has been demonstrated to apply in the transcriptional regulation of p130/E2F4 repressed genes involved in cell cycle progression.
We summarize in this review our current knowledge on the role of p27Kip1 in the regulation of transcription, on the transcriptional programs under its regulation and on its relevance in pathologies as cancer and neurodegeneration.
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