Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression.
Inhibition of cell growth by type beta transforming growth factor (TGF-beta) occurs in mid-G1 and is associated with decreased G1 cyclin-dependent kinase activity and maintenance of the retinoblastoma tumor suppressor protein Rb in an underphosphorylated, growth-suppressive state. A variety of recent experiments suggest that a functional target of Rb is the E2F transcription factor. In addition, the growth-suppressive effects of TGF-beta can be overcome by expression of viral oncogene products that dissociate E2F from Rb and Rb-related polypeptides. These results suggest the possibility that control of E2F may be a downstream event of TGF-beta action. Consistent with that possibility is the observation that E2F1 RNA levels are drastically reduced in TGF-beta-treated cells. We have also used a recombinant adenovirus containing the human E2F1 gene to overexpress the E2F1 product in mink lung epithelial cells that were growth arrested with TGF-beta. We find that overexpression of E2F1 can overcome the TGF-beta-mediated effect as measured by the activation of cellular DNA synthesis. These results suggest that a likely downstream target for the cyclin-dependent kinases, which are controlled by TGF-beta, is the activation of E2F.
Schwarz
J K
JK
Department of Genetics, Duke University Medical Center, Durham, NC 27710.
Bassing
C H
CH
Kovesdi
I
I
Datto
M B
MB
Blazing
M
M
George
S
S
Wang
X F
XF
Nevins
J R
JR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004847:Epithelial Cells; D005822:Genetic Vectors; D006801:Humans; D008168:Lung / Q000166:cytology; D008907:Mink; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D018844:Cyclin-Dependent Kinases