生物谷報道：乙酰轉(zhuǎn)移酶Tip60調(diào)控轉(zhuǎn)錄,，涉及DNA的損傷響應(yīng)?，F(xiàn)在,，它被發(fā)現(xiàn)在小鼠模型中和在人類腫瘤中都具有體內(nèi)腫瘤抑制活性,。人類Tip60位點(diǎn)（HTATIP）在頭部和頸部鱗狀細(xì)胞癌,、乳腺癌和淋巴癌中都經(jīng)常突變。在組織微陣列上著色的核Tip60在各種不同腫瘤中都丟失了,，而且最顯著的是在乳腺癌中也丟失了,。這項工作表明，要在初發(fā)腫瘤細(xì)胞中發(fā)起一個由致癌基因誘導(dǎo)的DNA損傷響應(yīng)，Tip60的濃度必須達(dá)到臨界水平：這一防衛(wèi)機(jī)制的失效可能與p53突變發(fā)生協(xié)同作用,，共同促進(jìn)腫瘤的發(fā)育,。
原始出處:
Nature 448, 1063-1067 (30 August 2007) | doi:10.1038/nature06055; Received 19 April 2007; Accepted 22 June 2007
Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response
Chiara Gorrini1,8, Massimo Squatrito1,8,9, Chiara Luise2, Nelofer Syed3, Daniele Perna1, Landon Wark4, Francesca Martinato1, Domenico Sardella1, Alessandro Verrecchia1, Samantha Bennett1, Stefano Confalonieri2, Matteo Cesaroni1, Francesco Marchesi5, Milena Gasco6, Eugenio Scanziani5, Maria Capra2, Sabine Mai4, Paolo Nuciforo2, Tim Crook3, John Lough7 & Bruno Amati1
Department of Experimental Oncology, European Institute of Oncology (IEO),
FIRC Institute of Molecular Oncology (IFOM), IFOM-IEO Campus, Milan 20139, Italy
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Chester Beatty Laboratories, London, SW3 6JB, UK
Manitoba Institute of Cell Biology and The Genomic Center for Cancer, Research and Diagnosis, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada
Department of Veterinary Pathology, Hygiene and Public Health, Section of Veterinary and Avian Pathology, University of Milan, Milan 20133, Italy
Department of Medical Oncology, San Croce e Carle Hospital, Cuneo 12100, Italy
Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
These authors contributed equally to this work.
Present address: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Correspondence to: Bruno Amati1 Correspondence and requests for materials should be addressed to B.A. (Email: [email protected]).
The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways1. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p532, 3, 4. Second, Tip60 modulates DNA-damage response (DDR) signalling1, and a DDR triggered by oncogenes can counteract tumour progression5, 6. Using E–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 DDR7, 8, 9 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 response10, 11, 12, 13. 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 pathway1, 2, 3, 14, 15, 16. We suggest that this is because critical levels of Tip60 are required for mounting an oncogene-induced DDR in incipient tumour cells5, 6, the failure of which might synergize with p53 mutation towards tumour progression17, 18, 19, 20.
