Amplification of the MYCN gene, resulting in overexpression of MYCN, distinguishes a subset of neuroblastomas with poor prognosis. The transcription factors driving MYCN expression in neuroblastomas are unknown. In transient-transfection assays, E2F-1, E2F-2, and E2F-3 activate a MYCN reporter construct dependent on the presence of several putative E2F-binding sites. Using chromatin immunoprecipitation, we show that E2F-1, E2F-2, and E2F-3 bind to the proximal MYCN promoter in vivo, specifically in neuroblastoma cell lines expressing MYCN. Inhibition of E2F activity in MYCNamplified cells by the overexpression of p16 INK4A reduced MYCN expression. In addition, we provide evidence that E2F proteins are involved in the negative regulation of MYCN by TGF- and retinoic acid. These data suggest that E2F transcription factors are critical for both the full activation and the repression of MYCN in neuroblastomas.The transcription factors encoded by the MYC genes form part of a complex regulatory network implicated in diverse tumorigenesis-relevant processes such as cell-cycle control, growth-factor dependence, response to antimitogenic signals, and apoptosis (1). Overexpression of the MYC genes as a result of chromosomal translocation, gene amplification, or loss of negative transcriptional control plays a prominent role in the etiology of many types of tumors. The evidence for a contribution of the MYC genes to tumorigenesis and the functional consequences of MYC overexpression have been the focus of several recent reviews (2, 3). Support for a critical role of MYC in cancer comes from several transgenic mouse models of MYCinduced tumorigenesis in which MYC expression can be reversibly switched off after tumors have developed (4 -6). Switching off MYC expression in the tumors resulted in tumor regression, suggesting that a tumor cell requires continuous MYC expression, although secondary genetic changes can obliterate this MYC dependence.The MYCN gene is found amplified in several types of childhood tumors of mostly neuroendocrine origin, including about 25% of neuroblastomas (7). Amplification results in overexpression of MYCN and distinguishes a subset of aggressive tumors with a poor prognosis (8). Together, these observations suggest that blocking MYCN expression may be beneficial for neuroblastoma patients. However, the development of a therapy based on this concept is hampered by our lack of understanding of the transcriptional regulation of the MYCN gene in neuroblastomas (9). Several signals that trigger neuronal differentiation of neuroblastoma cells, including pharmacological concentrations of all-trans retinoic acid, cause a repression of MYCN (10). This down-regulation of MYCN expression is essential for differentiation because ectopic expression of MYCN blocks differentiation (11). Neither the transcription factors nor the regulatory elements mediating the response to these signals have been identified as yet.The E2F transcription factors are important regulators of cell-cycle progression, and their acti...
The transcription factors encoded by the MYC genes control diverse tumorigenesis-relevant processes such as cell-cycle progression, growth factor dependence, and response to anti-mitogenic signals (for a review, see Refs. 1 and 2). Overexpression of one of the MYC genes as a result of chromosomal translocation, gene amplification, or loss of negative transcriptional control plays a prominent role in the etiology of many types of tumors (for a review, see Refs. 3 and 4). The MYCN gene is found amplified in several tumors of mostly neuroendocrine origin including about 25% of neuroblastomas, the most common solid tumor in childhood (for a review, see Refs. 5 and 6). Whereas many neuroblastomas regress spontaneously or can be cured with minimal therapy, MYCN-amplified tumors have a poor prognosis. The treatment of these patients has not improved significantly in the course of the last two decades. Recently, the comparison of the gene expression profiles of MYCN-expressing versus non-expressing neuroblastoma cells as well as MYCNamplified versus non-amplified primary tumors have begun to address the functional consequences of the massive overexpression of MYCN resulting from gene amplification (7,8).Several mouse models of Myc-induced tumorigenesis suggest that Myc is not only required for the initiation but also for the maintenance of the tumorigenic state supporting the value of the MYC genes as targets of tumor therapy (9 -11). Roughly half of the drugs that are in clinical use currently act as inhibitors of enzymes. In transcriptional regulation, enzymes are involved mainly as components of signal transduction cascades that relay information to the promoter and as transcriptional co-regulators that modulate local chromatin structure either by covalent modification of histones or by an ATPase-dependent remodeling of nucleosomes (for a review, see Ref. 12). The efficacy of histone deacetylase inhibitors against leukemia has proven the principle of treating cancer by the selective pharmacological modulation of the transcription machinery (13). Application of this concept to the MYCN gene requires a detailed knowledge of the molecular basis of the transcriptional activation of MYCN in neuroblastomas.Toward this goal, we have recently identified the activating members of the E2F family of transcription factors (E2F-1, E2F-2, and E2F-3) as regulators of MYCN expression in neuroblastomas (14). E2F proteins are important regulators of cell-cycle progression, and their activity is negatively controlled by the p16/Rb pathway, which is inactivated in the majority of human cancers (for a review, see Refs. 15 and 16). Although genetic defects of the p16/Rb pathway are rare in neuroblastomas, there is some evidence for a loss of normal control of E2F activity in neuroblastomas by epigenetic means (17).In addition to E2F binding sites, the MYCN promoter contains several putative binding sites for Sp1 and related zinc finger transcription factors (18). One of these, a non-consensus binding site, the CT-box, was previously impli...
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