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J. Biol. Chem., Vol. 280, Issue 23, 21915-21923, June 10, 2005

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p400 Is Required for E1A to Promote Apoptosis^*

Andrew V. Samuelson, Masako Narita, Ho-Man Chan¶||, Jianping Jin, Elisa de Stanchina**, Mila E. McCurrach, Masashi Narita, Miriam Fuchs, David M. Livingston, and Scott W. Lowe

From the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 and ^¶Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

The adenovirus E1A oncoprotein promotes proliferation and transformation by binding cellular proteins, including members of the retinoblastoma protein family, the p300/CREB-binding protein transcriptional coactivators, and the p400-TRRAP chromatin-remodeling complex. E1A also promotes apoptosis, in part, by engaging the ARF-p53 tumor suppressor pathway. We show that E1A induces ARF and p53 and promotes apoptosis in normal fibroblasts by physically associating with the retinoblastoma protein and a p400-TRRAP complex and that its interaction with p300 is largely dispensable for these effects. We further show that E1A increases p400 expression and, conversely, that suppression of p400 using stable RNA interference reduces the levels of ARF, p53, and apoptosis in E1A-expressing cells. Therefore, whereas E1A inactivates the retinoblastoma protein, it requires p400 to efficiently promote cell death. These results identify p400 as a regulator of the ARF-p53 pathway and a component of the cellular machinery that couples proliferation to cell death.

Received for publication, December 27, 2004 , and in revised form, February 22, 2005.

^* This work was supported by a grant from the NCI, National Institutes of Health (to D. M. L.) and NCI, National Institutes of Health Project Grant CA13106 (to S. W. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Department of Defense Breast Cancer Research Program predoctoral fellowship.

^|| Supported by a Human Frontier long term fellowship.

^** Supported by a Tularik postdoctoral fellowship.

Supported by a Department of Defense Breast Cancer Research Program postdoctoral fellowship and an Uehara Memorial Foundation research fellowship.

AACR-NFCR Research Professor. To whom correspondence should be addressed: Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724. Tel.: 516-367-8406; Fax: 516-367-8454; E-mail: lowe{at}cshl.org.

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