Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle.
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.
Miyake
S
S
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Sellers
W R
WR
Safran
M
M
Li
X
X
Zhao
W
W
Grossman
S R
SR
Gan
J
J
DeCaprio
J A
JA
Adams
P D
PD
Kaelin
W G
WG
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D003001:Cloning, Molecular; D015536:Down-Regulation; D051548:Histone Acetyltransferases; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D014452:Ubiquitins / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014452:Ubiquitins; D000123:Acetyltransferases; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D051736:Proto-Oncogene Proteins c-mdm2