TY - JOUR
T1 - The transcription factor E2F-1 modulates TGF-β1 RNA expression in glial cells
AU - Thatikunta, Prakash
AU - Raj, Ganesh V.
AU - Kundu, Mondira
AU - Khalili, Kamel
AU - Amini, Shohreh
N1 - Funding Information:
We gratefully thank Dr Joseph Nevins for kind gift of the adenovirus E2F, Dr Judith Campisi and Dr MJ Tevethia for the SV40 T-antigen mutants, Dr SJ Kim for the TGF-b deletion constructs, and Dr Arturo Sala and Dr David Hall for the E2F-1 mutant constructs. The authors express their gratitude to the past and present members of the Molecular Neurovirology Section of the Jefferson Institute of Molecular Medicine for their unflagging support, insightful discussions and invaluable materials. We also thank C Shriver and P Nicholson for preparation of this manuscript. This work was supported by a grant from NIH awarded to KK and SA.
PY - 1997
Y1 - 1997
N2 - The cell type specificity of the regulation of expression of the potent growth inhibitory cytokine transforming growth factor-beta (TGF-β), prompted our analyses of the regulation of TGF-β1 gene expression in glial cells by viral and cellular oncoproteins. We have shown that SV40 T-antigen diminished TGF-β1 expression in glial cells and this repression was dependent on the ability of T-antigen to interact with the tumor suppressor protein, pRb, and two structurally related proteins, p107 and p130. The cellular transcription factor E2F-1, which is a downstream effector of T-antigen, was unable to influence expression from the TGF-β1 promoter by itself. Interestingly, E2F-1 could overcome viral T-antigen-mediated repression of the TGF-β1 promoter, suggesting potential feedback loop between TGF-β and E2F in virally transformed glial cells. Using deletion analyses, we have mapped two E2F-1-responsive regions on the TGF-β1 promoter: a T-antigen-dependent negative regulatory sequence (TdNRS) between -323 and -175, and a T-antigen-independent positive regulatory sequence (TiPRS) between -34 and +10 on the TGF-β1 promoter. Further examination of TiPRS revealed the presence of a functional E2F binding site. Interestingly, the amino terminus of E2F-1 was required for its activation of TGF-β1 expression, as mutations in that domain abolished the ability of E2F-1 to increase TGF-β1 expression. These data suggest that yet-uncharacterized interaction between the amino terminus of E2F-1 and cellular proteins regulates TGF-β1 expression. The mechanism for E2F-1-mediated T-antigen-dependent regulation of TGF-β1 expression from TdNRS awaits further characterization.
AB - The cell type specificity of the regulation of expression of the potent growth inhibitory cytokine transforming growth factor-beta (TGF-β), prompted our analyses of the regulation of TGF-β1 gene expression in glial cells by viral and cellular oncoproteins. We have shown that SV40 T-antigen diminished TGF-β1 expression in glial cells and this repression was dependent on the ability of T-antigen to interact with the tumor suppressor protein, pRb, and two structurally related proteins, p107 and p130. The cellular transcription factor E2F-1, which is a downstream effector of T-antigen, was unable to influence expression from the TGF-β1 promoter by itself. Interestingly, E2F-1 could overcome viral T-antigen-mediated repression of the TGF-β1 promoter, suggesting potential feedback loop between TGF-β and E2F in virally transformed glial cells. Using deletion analyses, we have mapped two E2F-1-responsive regions on the TGF-β1 promoter: a T-antigen-dependent negative regulatory sequence (TdNRS) between -323 and -175, and a T-antigen-independent positive regulatory sequence (TiPRS) between -34 and +10 on the TGF-β1 promoter. Further examination of TiPRS revealed the presence of a functional E2F binding site. Interestingly, the amino terminus of E2F-1 was required for its activation of TGF-β1 expression, as mutations in that domain abolished the ability of E2F-1 to increase TGF-β1 expression. These data suggest that yet-uncharacterized interaction between the amino terminus of E2F-1 and cellular proteins regulates TGF-β1 expression. The mechanism for E2F-1-mediated T-antigen-dependent regulation of TGF-β1 expression from TdNRS awaits further characterization.
KW - Central nervous system
KW - E2F1
KW - Gene expression
KW - Oncoproteins
KW - TGF-β1
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U2 - 10.1038/sj.onc.1201129
DO - 10.1038/sj.onc.1201129
M3 - Article
C2 - 9205103
AN - SCOPUS:0030875599
SN - 0950-9232
VL - 14
SP - 2959
EP - 2969
JO - Oncogene
JF - Oncogene
IS - 24
ER -