Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts.

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.

• Authors: Hodaka Kitamura, Eiko Ozono, Ritsuko Iwanaga, Andrew P Bradford, Junko Okuno, Emi Shimizu, Kenta Kurayoshi, Kazuyuki Kugawa, Hiroyuki Toh, Kiyoshi Ohtani
• Journal: Genes to cells : devoted to molecular & cellular mechanisms (Genes Cells) Vol. 20 Issue 9 Pg. 739-57 (Sep 2015) ISSN: 1365-2443 [Electronic] England
• PMID: 26201719 (Publication Type: Journal Article)
• Copyright: © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• E2F Transcription Factors
• E2F1 Transcription Factor
• Membrane Proteins
• Proto-Oncogene Proteins

Topics

• Apoptosis
• Apoptosis Regulatory Proteins (genetics)
• Bcl-2-Like Protein 11
• Cell Line
• E2F Transcription Factors (metabolism)
• E2F1 Transcription Factor (metabolism)
• Fibroblasts (metabolism)
• Genes, Tumor Suppressor
• Membrane Proteins (genetics)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins (genetics)