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Published on: June 27, 2020
Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts
Hodaka Kitamura1, Eiko Ozono2, Ritsuko Iwanaga3
1Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.
Abstract:
The transcription factor E2F is the principal target of the tumor suppressor pRB. E2F plays crucial roles not only in cell proliferation by activating growth-related genes but also in tumor suppression by activating pro-apoptotic and growth-suppressive genes. We previously reported that, in human normal fibroblasts, the tumor suppressor genes ARF, p27(Kip1) and TAp73 are activated by deregulated E2F activity induced by forced inactivation of pRB, but not by physiological E2F activity induced by growth stimulation. In contrast, growth-related E2F targets are activated by both E2F activities, underscoring the roles of deregulated E2F in tumor suppression in the context of dysfunctional pRB. In this study, to further understand the roles of deregulated E2F, we explored new targets that are specifically activated by deregulated E2F using DNA microarray. The analysis identified nine novel targets (BIM, RASSF1, PPP1R13B, JMY, MOAP1, RBM38, ABTB1, RBBP4 and RBBP7), many of which are involved in the p53 and RB tumor suppressor pathways. Among these genes, the BIM gene was shown to be activated via atypical E2F-responsive promoter elements and to contribute to E2F1-mediated apoptosis. Our results underscore crucial roles of deregulated E2F in growth suppression to counteract loss of pRB function.
Insights
Deregulated E2F activity, often seen with dysfunctional pRB, activates specific tumor suppressor genes, including novel targets like BIM, crucial for growth suppression and counteracting cancer progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Cycle Regulation
Background:
- The retinoblastoma protein (pRB) tumor suppressor pathway is frequently inactivated in human cancers.
- The transcription factor E2F is a key target of pRB and regulates cell proliferation and tumor suppression.
- Deregulated E2F activity, resulting from pRB inactivation, can trigger tumor suppressor gene expression.
Purpose of the Study:
- To identify novel target genes specifically activated by deregulated E2F activity.
- To understand the role of deregulated E2F in tumor suppression beyond known targets.
- To investigate the mechanism of BIM gene activation by E2F and its role in apoptosis.
Main Methods:
- DNA microarray analysis to identify novel E2F target genes.
- Quantitative PCR and Western blotting to validate gene expression and protein levels.
- Reporter assays to confirm E2F-responsive promoter elements and functional analysis of BIM in apoptosis.
Main Results:
- Nine novel genes (BIM, RASSF1, PPP1R13B, JMY, MOAP1, RBM38, ABTB1, RBBP4, RBBP7) were identified as specifically activated by deregulated E2F.
- These novel targets are frequently involved in the p53 and RB tumor suppressor pathways.
- BIM is activated by atypical E2F-responsive elements and contributes to E2F1-induced apoptosis.
Conclusions:
- Deregulated E2F activity plays a critical role in activating specific tumor suppressor genes, contributing to growth suppression.
- The identified novel targets highlight the complex network regulated by E2F in tumor suppression.
- Understanding these E2F-mediated pathways offers potential therapeutic strategies for cancers with pRB dysfunction.
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