p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

The E2F family of transcription factors plays a key role in regulating cell-cycle progression. Accordingly, E2F is itself tightly controlled by a series of transcriptional and posttranscriptional events. Here we provide evidence that E2F1 protein levels are regulated by the ubiquitin–proteasome-dependent degradation pathway. An analysis of E2F1 mutants identified a conserved carboxyl-terminal region, which is required for eliciting ubiquitination and protein turnover. Fusion of this E2F1 carboxyl-terminal sequence to a heterologous protein, GAL4, resulted in destabilization of GAL4. Previous studies identified an overlapping region of E2F1 that facilitates complex formation with retinoblastoma tumor suppressor protein, pRB, and we found that pRB blocks ubiquitination and stabilizes E2F1. These results suggest a new mechanism for controlling the cell-cycle regulatory activity of E2F1.

E2F

Retinoblastoma protein

E2F1

10.1073/pnas.94.6.2221

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Citations (198)

Regulation of the G1/S transition phase in mesangial cells by E2F1

Kidney International (1999)

Seiji Inoshita Yoshio Terada Osamu Nakashima Michio Kuwahara S. Sasaki

E2F

E2F1

Retinoblastoma protein

Cyclin E

Cyclin A

Mesangial cell

Cyclin D

10.1046/j.1523-1755.1999.00705.x

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Citations (50)

E2F1 is crucial for E2F‐dependent apoptosis

EMBO Reports (2005)

Eros Lazzerini Denchi Kristian Helin

E2F1

E2F

Ectopic expression

Retinoblastoma

Retinoblastoma protein

10.1038/sj.embor.7400452

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Citations (112)

Characterization of an E2F1-specific binding domain in pRB and its implications for apoptotic regulation

Oncogene (2007)

Lisa M. Julian Oliva Palander Laurie Seifried Julia Foster Frederick A. Dick

E2F

E2F1

Retinoblastoma protein

Retinoblastoma

10.1038/sj.onc.1210803

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Citations (43)

Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry

Nature Genetics (2002)

Marina Lomazzi Maria Cristina Moroni Michael Rugaard Jensen Emanuela Frittoli Kristian Helin

E2F

Retinoblastoma protein

E2F1

Retinoblastoma

10.1038/ng891

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Citations (80)

The Cellular Effects of E2F Overexpression

Current topics in microbiology and immunology (1996)

Peter D. Adams William G. Kaelin

E2F

E2F1

Retinoblastoma protein

Retinoblastoma

10.1007/978-3-642-79910-5_4

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Citations (119)

INVESTIGATING THE ROLE AND REGULATION OF THE SPECIFIC ANDGENERAL PRB-E2F1 INTERACTIONS

Clinical and investigative medicine (2008)

Matthew J. Cecchini Frederick A. Dick

Background/Purpose. The retinoblastoma tumor suppressor protein (pRB) plays a central role in proliferative control and is a frequent target for inactivation in cancer. The G1-Sphase transition of the cell cycle is regulated by pRB, which is capable of interacting with E2F family members and inhibiting the transcription of genesrequired to progress into S-phase. E2F1 is unique from other E2F family members as it can induce both apoptosis and proliferation. To control these contrasting functions of E2F1, a second E2F1 binding site exists in the C-terminus of pRB that can control apoptosis separately from proliferation. This anti-apoptotic function of pRBcan in some circumstances promote tumorigenesis, which leads to the question; is pRB a tumor suppressor or an oncogene? Methods. To investigate this, a gene-targeted mouse model is being engineered to selectively disrupt the ability of pRB to control proliferation through the general E2F binding site while still retaining the ability tocontrol apoptosis through the specific E2F1 site. Results. A series of novel mutants were engineered to selectively disrupt the binding of E2Fs at the general site, and prevent pRB from controlling proliferation. The mutants retain the ability to bind E2F1 and control apoptosis through thespecific binding site, which is not disrupted. Conclusions. By separating the ability of pRB to control proliferation and apoptosis under in vivo conditions, a better understanding into the significance of these two functions in development and tumorigenesis can be gained.

E2F1

E2F

Retinoblastoma protein

Retinoblastoma

10.25011/cim.v31i4.4795

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Citations (0)

The retinoblastoma protein as a transcriptional repressor

Trends in Cell Biology (1993)

Kristian Helin Ed Harlow

E2F

Retinoblastoma protein

E2F1

Retinoblastoma

Transcription

10.1016/0962-8924(93)90150-y

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Citations (176)

E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos

Genes & Development (2001)

Ulrike Ziebold Tammi L. Reza Alicia Caron Jacqueline A. Lees

The E2F transcription factors are thought to be key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. It is widely believed that E2F1, E2F2, and E2F3 can all activate cellular proliferation but that E2F1 is the specific inducer of apoptosis. Here we show that the E2f3 mutation completely suppresses both the inappropriate proliferation and the p53-dependent apoptosis arising in the Rb mutant embryos. Through the analysis of Rb −/− ;E2f3 +/− embryos, we have been able to separate E2F3's role in the induction of apoptosis from its ability to induce proliferation. Thus, contrary to the prevailing view of E2F action, E2F3 makes a major contribution to the apoptosis resulting from pRB loss.

E2F1

E2F

Retinoblastoma protein

Retinoblastoma

Inducer

10.1101/gad.858801

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Citations (201)

Proapoptotic Function of the Retinoblastoma Tumor Suppressor Protein

Cancer Cell (2009)

Alessandra Ianari Tiziana Natale Eliezer Calo Elisabetta Ferretti Edoardo Alesse

Retinoblastoma protein