Abstract
The transcription factor E2F plays crucial roles in cell proliferation and tumor suppression by activating growth-related genes and pro-apoptotic tumor suppressor genes, respectively. It is generally accepted that E2F binds to target sequences with its heterodimeric partner DP. Here we show that, while knockdown of DP1 expression inhibited ectopic E2F1- or adenovirus E1a-induced expression of the CDC6 gene and cell proliferation, knockdown of DP1 and DP2 expression did not affect ectopic E2F1- or E1a-induced expression of the tumor suppressor ARF gene, an upstream activator of the tumor suppressor p53, activation of p53 or apoptosis. These observations suggest that growth related and pro-apoptotic E2F targets are regulated by distinct molecular mechanisms and contradict the threshold model, which postulates that E2F activation of pro-apoptotic genes requires a higher total activity of activator E2Fs, above that necessary for E2F-dependent activation of growth-related genes.
Highlights
E2F family proteins (E2F1-E2F5) form heterodimeric complexes with DP family proteins (DP1 and DP2), generating E2F transcriptional activity that regulates expression of growth-related target genes[1,2,3]
The ARF promoter responds to deregulated E2F activity induced by ectopic expression of E2F1 or inactivation of pRB by adenovirus E1a or short hairpin RNA, but not to physiological E2F activity induced by serum stimulation
ShRNA-mediated down regulation of DP1 alone, in human fibroblasts or the corresponding ortholog in Drosophila, is sufficient to inhibit binding of E2F to typical E2F binding sequences, leading to a reduction in growth-related target gene expression and cell cycle progression[4,5]
Summary
E2F family proteins (E2F1-E2F5) form heterodimeric complexes with DP family proteins (DP1 and DP2), generating E2F transcriptional activity that regulates expression of growth-related target genes[1,2,3]. Tissue specific inactivation of p53, when combined with pRB inactivation, promotes the development of lung and ovarian tumors in mice[15,16] These observations suggest that E2F regulation of the ARF-p53 pathway is crucial for prevention of tumorigenesis resulting from dysfunction of pRB. The ARF promoter responds to deregulated E2F activity induced by ectopic expression of E2F1 or inactivation of pRB by adenovirus E1a or short hairpin RNA (shRNA), but not to physiological E2F activity induced by serum stimulation. Growth-related target promoters, on the other hand, are activated by all of these stimuli These observations suggest that the ability of the ARF promoter to discriminate between physiological and deregulated E2F activity serves as the basis for the ARF gene to function as a tumor suppressor gene in response to dysfunction of pRB17.
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