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The transcription factor E2F-1 modulates TGF-beta1 RNA expression in glial cells
P Thatikunta1, G V Raj, M Kundu
1Center for Neurovirology, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19107, USA.
Oncogene
|June 19, 1997
Summary
SV40 T-antigen represses TGF-beta1 expression in glial cells via pRb family proteins. E2F-1 can overcome this repression, suggesting a feedback loop involving TGF-beta and E2F in viral glial transformation.
Area of Science:
- Molecular Biology
- Cell Biology
- Virology
Background:
- Transforming growth factor-beta (TGF-beta) is a potent cytokine with cell-type-specific regulatory functions.
- Viral and cellular oncoproteins can influence the expression of growth-regulatory genes like TGF-beta1.
- Glial cells play crucial roles in the central nervous system and are susceptible to viral transformation.
Purpose of the Study:
- To investigate the regulation of TGF-beta1 gene expression in glial cells by viral oncoproteins, specifically SV40 T-antigen.
- To elucidate the role of the cellular transcription factor E2F-1 in mediating TGF-beta1 expression and its interaction with viral oncoproteins.
Main Methods:
- Deletion analyses of the TGF-beta1 promoter to identify regulatory regions.
- Assays to assess the interaction between SV40 T-antigen, pRb family proteins, and E2F-1.
- Mutational analysis of E2F-1 to determine functional domains involved in TGF-beta1 regulation.
Main Results:
- SV40 T-antigen repressed TGF-beta1 expression in glial cells, dependent on its interaction with pRb, p107, and p130.
- E2F-1 alone did not affect TGF-beta1 promoter activity but could overcome T-antigen-mediated repression.
- Two E2F-1-responsive regions were mapped: a T-antigen-dependent negative regulatory sequence (TdNRS) and a T-antigen-independent positive regulatory sequence (TiPRS) containing an E2F binding site.
- The amino terminus of E2F-1 was essential for its ability to activate TGF-beta1 expression.
Conclusions:
- SV40 T-antigen-mediated repression of TGF-beta1 in glial cells involves interactions with pRb family proteins.
- A potential feedback loop exists between TGF-beta and E2F in virally transformed glial cells.
- Regulation of TGF-beta1 expression by E2F-1 involves its amino terminus and interactions with unknown cellular proteins, with specific regulatory elements on the TGF-beta1 promoter.