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Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts
Author(s) -
Kitamura Hodaka,
Ozono Eiko,
Iwanaga Ritsuko,
Bradford Andrew P.,
Okuno Junko,
Shimizu Emi,
Kurayoshi Kenta,
Kugawa Kazuyuki,
Toh Hiroyuki,
Ohtani Kiyoshi
Publication year - 2015
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12268
Subject(s) - e2f , biology , transcription factor , microbiology and biotechnology , suppressor , cancer research , gene , tumor suppressor gene , e2f1 , genetics , carcinogenesis
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 TA p73 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 , RASSF 1 , PPP 1R13B , JMY , MOAP 1 , RBM 38 , ABTB 1 , RBBP 4 and RBBP 7 ), 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.