E2F-1:DP-1 induces p53 and overrides survival factors to trigger apoptosis.
The E2F DNA binding activity consists of a heterodimer between E2F and DP family proteins, and these interactions are required for association of E2F proteins with pRb and the pRb-related proteins p107 and p130, which modulate E2F transcriptional activities. E2F-1 expression is sufficient to release fibroblasts from G0 and induce entry into S phase, yet it also initiates apoptosis. To investigate the mechanisms of E2F-induced apoptosis, we utilized interleukin-3 (IL-3)-dependent 32D.3 myeloid cells, a model of hematopoietic progenitor programmed cell death. In the absence of IL-3, E2F-1 alone was sufficient to induce apoptosis, and p53 levels were diminished. DP-1 alone was not sufficient to induce cell cycle progression or alter rates of death following IL-3 withdrawal. However, overexpression of both E2F-1 and DP-1 led to the rapid death of cells even in the presence of survival factors. In the presence of IL-3, levels of endogenous wild-type p53 increased in response to E2F-1, and coexpression of DP-1 further augmented p53 levels. These results provide evidence that E2F is a functional link between the tumor suppressors p53 and pRb. However, induction of p53 alone was not sufficient to trigger apoptosis, suggesting that the ability of E2F to override survival factors involves additional effectors.
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
S W
SW
Hiebert
G
G
Packham
D K
DK
Strom
R
R
Haffner
M
M
Oren
G
G
Zambetti
J L
JL
Cleveland
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005347:Fibroblasts; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D013997:Time Factors; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007377:Interleukin-3; D011994:Recombinant Proteins; D056465:Retinoblastoma-Binding Protein 1; C493735:TFDP1 protein, human; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone