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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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