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Molecular and Cellular Biology, August 2005, p. 6639-6648, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6639-6648.2005

ING2 Regulates the Onset of Replicative Senescence by Induction of p300-Dependent p53 Acetylation{dagger}

Remy Pedeux,1 Sagar Sengupta,1,6 Jiang Cheng Shen,1 Oleg N. Demidov,2 Shin'ichi Saito,2 Hitoshi Onogi,1 Kensuke Kumamoto,1 Stephen Wincovitch,3 Susan H. Garfield,3 Mary McMenamin,1 Makoto Nagashima,1,4 Steven R. Grossman,5 Ettore Appella,2 and Curtis C. Harris1*

Laboratory of Human Carcinogenesis,1 Laboratory of Cell Biology,2 Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,3 Department of Surgery, Toho University Sakura Hospital, Sakura, Japan,4 Departments of Cancer Biology and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts,5 National Institute of Immunology, Aruna Asaf Marg, New Delhi, India6

Received 3 December 2004/ Returned for modification 13 January 2005/ Accepted 6 May 2005

ING2 is a candidate tumor suppressor gene that can activate p53 by enhancing its acetylation. Here, we demonstrate that ING2 is also involved in p53-mediated replicative senescence. ING2 protein expression increased in late-passage human primary cells, and it colocalizes with serine 15-phosphorylated p53. ING2 and p53 also complexed with the histone acetyltransferase p300. ING2 enhanced the interaction between p53 and p300 and acted as a cofactor for p300-mediated p53 acetylation. The level of ING2 expression directly modulated the onset of replicative senescence. While overexpression of ING2 induced senescence in young fibroblasts in a p53-dependent manner, expression of ING2 small interfering RNA delayed the onset of senescence. Hence, ING2 can act as a cofactor of p300 for p53 acetylation and thereby plays a positive regulatory role during p53-mediated replicative senescence.

* Corresponding author. Mailing address: Laboratory of Human Carcinogenesis, CCR, NCI, NIH, 37 Convent Dr., Bldg 37, Room 3068, Bethesda, MD 20892-4255. Phone: (301) 496-2048 Fax: (301) 496-0497. E-mail: Curtis_Harris{at}nih.gov.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 6639-6648, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6639-6648.2005




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