E2F4 loss suppresses tumorigenesis in Rb mutant mice.
The E2F transcription factors mediate the activation or repression of key cell cycle regulatory genes under the control of the retinoblastoma protein (pRB) tumor suppressor and its relatives, p107 and p130. Here we investigate how E2F4, the major "repressive" E2F, contributes to pRB's tumor-suppressive properties. Remarkably, E2F4 loss suppresses the development of both pituitary and thyroid tumors in Rb(+/-) mice. Importantly, E2F4 loss also suppresses the inappropriate gene expression and proliferation of pRB-deficient cells. Biochemical analyses suggest that this tumor suppression occurs via a novel mechanism: E2F4 loss allows p107 and p130 to regulate the pRB-specific, activator E2Fs. We also detect these novel E2F complexes in pRB-deficient cells, suggesting that they play a significant role in the regulation of tumorigenesis in vivo.
Lee
Eunice Y
EY
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cam
Hieu
H
Ziebold
Ulrike
U
Rayman
Joseph B
JB
Lees
Jacqueline A
JA
Dynlacht
Brian David
BD
D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D019927:Cyclin E / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D050704:E2F4 Transcription Factor; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics; D011506:Proteins; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics*; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
D019927:Cyclin E; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors