title: TRIM8 modulates p53 activity to dictate cell cycle arrest.
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. We described here that the human TRIM8 protein, a member of the TRIM family, is a new modulator of the p53-mediated tumor suppression mechanism. We showed 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.
authors.affiliation: Institute for Biomedical Technologies, National Research Council, Bari, Italy.
authors.forename: Mariano Francesco
authors.initials: MF
authors.lastname: Caratozzolo
authors.forename: Lucia
authors.initials: L
authors.lastname: Micale
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Turturo
authors.forename: Silvia
authors.initials: S
authors.lastname: Cornacchia
authors.forename: Carmela
authors.initials: C
authors.lastname: Fusco
authors.forename: Flaviana
authors.initials: F
authors.lastname: Marzano
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Augello
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: D'Erchia
authors.forename: Luisa
authors.initials: L
authors.lastname: Guerrini
authors.forename: Graziano
authors.initials: G
authors.lastname: Pesole
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Sbisà
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Merla
authors.forename: Apollonia
authors.initials: A
authors.lastname: Tullo
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004260:DNA Repair; D045325:HCT116 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C418604:TRIM8 protein, human