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Molecular and Cellular Biology, December 2000, p. 8889-8902, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cells Degrade a Novel Inhibitor of Differentiation with E1A-Like Properties upon Exiting the Cell Cycle

Satoshi Miyake,1,2 William R. Sellers,1 Michal Safran,1 Xiaotong Li,1 Wenqing Zhao,3 Steven R. Grossman,3 Jianmin Gan,1 James A. DeCaprio,1 Peter D. Adams,4 and William G. Kaelin Jr.1,2,*

Department of Adult Oncology,1 Department of Cancer Biology,3 and Howard Hughes Medical Institute,2 Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, and Department of Molecular Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 191114

Received 8 May 2000/Returned for modification 10 July 2000/Accepted 15 September 2000

Control of proliferation and differentiation by the retinoblastoma tumor suppressor protein (pRB) and related family members depends upon their interactions with key cellular substrates. Efforts to identify such cellular targets led to the isolation of a novel protein, EID-1 (for E1A-like inhibitor of differentiation 1). Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. EID-1 is rapidly degraded by the proteasome as cells exit the cell cycle. Ubiquitination of EID-1 requires an intact C-terminal region that is also necessary for stable binding to p300 and pRB, two proteins that bind to the ubiquitin ligase MDM2. A pRB variant that can bind to EID1, but not MDM2, stabilizes EID-1 in cells. Thus, EID-1 may act at a nodal point that couples cell cycle exit to the transcriptional activation of genes required for differentiation.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115. Phone: (617) 632-3975. Fax: (617) 632-4760. E-mail: william_kaelin{at}dfci.harvard.edu.

Molecular and Cellular Biology, December 2000, p. 8889-8902, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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