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Role of p27Kip1 as a transcriptional regulator

2018; Impact Journals LLC; Volume: 9; Issue: 40 Linguagem: Inglês

10.18632/oncotarget.25447

1949-2553

Oriol Bachs, Edurne Gallastegui, Serena Orlando, Anna Bigas, José Manuel Morante‐Redolat, Joan Serratosa, Isabel Fariñas, Rosa Aligué, María Jesús Pujol,

Genomics and Chromatin Dynamics

// Oriol Bachs 1 , Edurne Gallastegui 1 , Serena Orlando 1 , Anna Bigas 2 , José Manuel Morante-Redolat 3 , Joan Serratosa 4 , Isabel Fariñas 3 , Rosa Aligué 1 and Maria Jesús Pujol 1 1 Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, IDIBAPS, CIBERONC, Barcelona, Spain 2 Program in Cancer Research, Institut Hospital Del Mar d'Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain 3 Departamento de Biología Celular, Biología Funcional y Antropología Física and ERI de Biotecnología y Biomedicina, CIBERNED, Universidad de Valencia, Valencia, Spain 4 Department of Cerebral Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Barcelona, Spain Correspondence to: Oriol Bachs, email: obachs@ub.edu Keywords: p27 Kip1 ; transcriptional regulation; cancer; neurodegeneration Received: November 08, 2017 Accepted: May 01, 2018 Published: May 25, 2018 ABSTRACT The protein p27 Kip1 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. p27 Kip1 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 p27 Kip1 . Thus, important cellular functions as cell division cycle, respiration, RNA processing, translation and cell adhesion, are under p27 Kip1 regulation. Moreover, genes involved in pathologies as cancer and neurodegeneration are also regulated by p27 Kip1 , suggesting its implication in these pathologies. The carboxyl moiety of p27 Kip1 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 p27 Kip1 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 p27 Kip1 in the regulation of transcription, on the transcriptional programs under its regulation and on its relevance in pathologies as cancer and neurodegeneration.