Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis.
Deregulation of the Myc pathway and deregulation of the Rb pathway are two of the most common abnormalities in human malignancies. Recent in vitro experiments suggest a complex cross-regulatory relationship between Myc and Rb that is mediated through the control of E2F. To evaluate the functional connection between Myc and E2Fs in vivo, we used a bitransgenic mouse model of Myc-induced T cell lymphomagenesis and analyzed tumor progression in mice deficient for E2f1, E2f2, or E2f3. Whereas the targeted inactivation of E2f1 or E2f3 had no significant effect on tumor progression, loss of E2f2 accelerated lymphomagenesis. Interestingly, loss of a single copy of E2f2 also accelerated tumorigenesis, albeit to a lesser extent, suggesting a haploinsufficient function for this locus. The combined ablation of E2f1 or E2f3, along with E2f2, did not further accelerate tumorigenesis. Myc-overexpressing T cells were more resistant to apoptosis in the absence of E2f2, and the reintroduction of E2F2 into these tumor cells resulted in an increase of apoptosis and inhibition of tumorigenesis. These results identify the E2f2 locus as a tumor suppressor through its ability to modulate apoptosis.
Opavsky
Rene
R
Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210, USA.
Tsai
Shih-Yin
SY
Guimond
Martin
M
Arora
Anjulie
A
Opavska
Jana
J
Becknell
Brian
B
Kaufmann
Michael
M
Walton
Nathaniel A
NA
Stephens
Julie A
JA
Fernandez
Soledad A
SA
Muthusamy
Natarajan
N
Felsher
Dean W
DW
Porcu
Pierluigi
P
Caligiuri
Michael A
MA
Leone
Gustavo
G
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D050699:E2F3 Transcription Factor / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D016271:Proto-Oncogene Proteins c-myc