Faculty Collaboration Database

Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 2007 Aug 30;448(7157):1063-7

Date

08/31/2007

Pubmed ID

17728759

DOI

10.1038/nature06055

Scopus ID

2-s2.0-34548312368 (requires institutional sign-in at Scopus site)   281 Citations

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.

Author List

Gorrini C, Squatrito M, Luise C, Syed N, Perna D, Wark L, Martinato F, Sardella D, Verrecchia A, Bennett S, Confalonieri S, Cesaroni M, Marchesi F, Gasco M, Scanziani E, Capra M, Mai S, Nuciforo P, Crook T, Lough J, Amati B

Author

John W. Lough PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
B-Lymphocytes
Carcinoma
Cells, Cultured
DNA Damage
Genes, Tumor Suppressor
Genes, myc
Heterozygote
Histone Acetyltransferases
Homeostasis
Humans
Lymphoma
Lysine Acetyltransferase 5
Mice
Mice, Transgenic
Oncogene Protein p55(v-myc)
Oncogenes
Trans-Activators
Transcription, Genetic
Tumor Suppressor Protein p53
Tumor Suppressor Proteins