title: Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response.
abstract: The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p53. Second, Tip60 modulates DNA-damage response (DDR) signalling, and a DDR triggered by oncogenes can counteract tumour progression. Using E(mu)-myc transgenic mice that are heterozygous for a Tip60 gene (Htatip) knockout allele (hereafter denoted as Tip60+/- mice), we show that Tip60 counteracts Myc-induced lymphomagenesis in a haplo-insufficient manner and in a time window that is restricted to a pre- or early-tumoral stage. Tip60 heterozygosity severely impaired the Myc-induced DDR but caused no general DDR defect in B cells. Myc- and p53-dependent transcription were not affected, and neither were Myc-induced proliferation, activation of the ARF-p53 tumour suppressor pathway or the resulting apoptotic response. We found that the human TIP60 gene (HTATIP) is a frequent target for mono-allelic loss in human lymphomas and head-and-neck and mammary carcinomas, with concomitant reduction in mRNA levels. Immunohistochemical analysis also demonstrated loss of nuclear TIP60 staining in mammary carcinomas. These events correlated with disease grade and frequently concurred with mutation of p53. Thus, in both mouse and human, Tip60 has a haplo-insufficient tumour suppressor activity that is independent from-but not contradictory with-its role within the ARF-p53 pathway. We suggest that this is because critical levels of Tip60 are required for mounting an oncogene-induced DDR in incipient tumour cells, the failure of which might synergize with p53 mutation towards tumour progression.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Milan 20139, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gorrini
authors.forename: Massimo
authors.initials: M
authors.lastname: Squatrito
authors.forename: Chiara
authors.initials: C
authors.lastname: Luise
authors.forename: Nelofer
authors.initials: N
authors.lastname: Syed
authors.forename: Daniele
authors.initials: D
authors.lastname: Perna
authors.forename: Landon
authors.initials: L
authors.lastname: Wark
authors.forename: Francesca
authors.initials: F
authors.lastname: Martinato
authors.forename: Domenico
authors.initials: D
authors.lastname: Sardella
authors.forename: Alessandro
authors.initials: A
authors.lastname: Verrecchia
authors.forename: Samantha
authors.initials: S
authors.lastname: Bennett
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchesi
authors.forename: Milena
authors.initials: M
authors.lastname: Gasco
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Maria
authors.initials: M
authors.lastname: Capra
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.forename: Tim
authors.initials: T
authors.lastname: Crook
authors.forename: John
authors.initials: J
authors.lastname: Lough
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage; D016147:Genes, Tumor Suppressor; D016259:Genes, myc / Q000235:genetics; D006579:Heterozygote; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008822:Mice, Transgenic; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics*; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016274:Oncogene Protein p55(v-myc); D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5