TRIM8 modulates p53 activity to dictate cell cycle arrest

Mariano Francesco Caratozzolo, Lucia Micale, Maria Giuseppina Turturo, Silvia Cornacchia, Carmela Fusco, Flaviana Marzano, Bartolomeo Augello, Anna Maria D'Erchia, Luisa Guerrini, Graziano Pesole, Elisabetta Sbisà, Giuseppe Merla, Apollonia Tullo

Research output: Contribution to journalArticle

Abstract

p53 is a central hub in controlling cell proliferation. To maintain genome integrity in response to cellular stress, p53 directly regulates the transcription of genes involved in cell cycle arrest, DNA repair, apoptosis and/or senescence. An array of post-translational modifications and protein-protein interactions modulates its stability and activities in order to avoid malignant transformation. However, to date, it is still not clear how cells decide their own fate in response to different types of stress. Here we describe that the human TRIM8 protein, a member of the TRIM family, is a new modulator of the p53-mediated tumor suppression mechanism. We show that under stress conditions, such as UV exposure, p53 induced the expression of TRIM8, which, in turn, stabilized p53, leading to cell cycle arrest and reduction of cell proliferation through enhancement of CDKN1A (p21) and GADD45 expression. TRIM8 silencing reduced the capacity of p53 to activate genes involved in cell cycle arrest and DNA repair in response to cellular stress. Concurrently, TRIM8 overexpression induced the degradation of the MDM2 protein, the principal regulator of p53 stability. Co-immunoprecipitation experiments showed that TRIM8 physically interacted with p53, impairing its interaction with MDM2. Altogether, our results reveal a previously unknown regulatory pathway controlling p53 activity and suggest TRIM8 as a novel therapeutic target to enhance p53 tumor suppressor activity.

Original languageEnglish
Pages (from-to)511-523
Number of pages13
JournalCell Cycle
Volume11
Issue number3
DOIs
Publication statusPublished - Feb 1 2012

Keywords

  • Cell fate
  • p53
  • Stress response
  • TRIM8
  • Tumor suppressor

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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  • Cite this

    Caratozzolo, M. F., Micale, L., Turturo, M. G., Cornacchia, S., Fusco, C., Marzano, F., Augello, B., D'Erchia, A. M., Guerrini, L., Pesole, G., Sbisà, E., Merla, G., & Tullo, A. (2012). TRIM8 modulates p53 activity to dictate cell cycle arrest. Cell Cycle, 11(3), 511-523. https://doi.org/10.4161/cc.11.3.19008