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Background: Nuclear respiratory factor 1 (NRF1), historically perceived as a protein regulating genes controlling mitochondrial biogenesis, is now widely recognized as a multifunctional protein and as a key player in the transcriptional modulation of genes implicated in various cellular functions. Here, we present emerging data supporting novel roles of NRF1 in cancer development and progression through its interplay with the transcription factors E2F4 and MYC. To identify common human NRF1, E2F4 and MYC target genes, we analyzed the Encyclopedia of DNA Elements (ENCODE) NRF1 ChIP-Seq data. By doing so, we identified 9253 common target genes with NRF1, E2F4 and MYC binding motifs. NRF1 binding motifs were found to be present in genes operating in signaling pathways governing all hallmarks of malignant transformation and progression, including proliferation, invasion, self-renewal and apoptosis.Conclusions: In addition to controlling mitochondrial biogenesis NRF1, in conjunction with E2F4 and MYC, may play a critical role in the acquisition of human cancer characteristics. Additionally, NRF1 may orchestrate both MYC and E2F4 to regulate common target genes linked to multiple networks in the development and progression of cancer. A comprehensive understanding of this dynamic interplay will set the stage, not only for the design of novel treatment strategies, but also for the discovery of pan-cellular transcription factor regulatory strategies to predict cancer risk, therapy response and patient prognosis. [ABSTRACT FROM AUTHOR]

p130/E2f4 suppressor complex inhibits the transcription of multiple genes that regulate the cell cycle and induces cell cycle arrest at G0/G1. This is a requirement for the initiation of cell differentiation in many tissues. Here, we found that the activation of the Wnt/β-catenin signaling in mesenchymal stem cells (MSC) induced by their coculture with the A-549 cells line or by growth in medium containing Li ions resulted in the accumulation of active forms of p130, E2f4, and β-catenin not coupled with the inhibition of the cell cycle. The synchronization of the MSC cell cycle produced by thymidine and nocodazole did not change the level and phosphorylation pattern of p130. Unlike MSC mouse hepatocytes and T98G cells accumulated the p1 and p2 forms of p130 in the quiescent state and the p3 form during active proliferation. Antibodies to p130 precipitated β-catenin from extracts of MSC, while antibodies to β-catenin precipitated p130. The data obtained suggest that Gsk3β, p130, and β-catenin form a complex in MSC. The functional role of this complex may be associated with the activation of differentiation not coupled with cell cycle arrest. [ABSTRACT FROM AUTHOR]

Identification and characterization of tumor subtypes using gene expression profiles of triple negative breast cancer patients. Microarray data of four breast cancer studies were pooled and evaluated. Molecular subtype classification was performed using random forest and a novel algorithm for feature extraction via composite scoring and voting. Biological and clinical properties were evaluated via GSEA, functional annotation clustering and clinical endpoint analysis. The subtype signatures are highly predictive for distant metastasis free survival of tamoxifen-treated patients. Consensus clustering and the novel algorithm proposed three triple negative subtypes. One subtype shows low E2F4 gene expression and is predictive for survival of ER negative breast cancer patients. The other two subtypes share commonalities with luminal B tumors. Classification of breast cancer expression profiles may reveal novel tumor subtypes, possessing clinical impact. Furthermore, subtype characterizing gene signatures might hold potential for novel strategies in cancer therapy. [ABSTRACT FROM AUTHOR]

Coordination of proliferation and differentiation in cells committed to muscle fate requires the interaction of the retinoblastoma gene product (pRb) with transcription factors of the E2F family, pRb having different affinities for distinct E2Fs. It was found that pRb carrying a small deletion at the end of the T antigen-binding region (ΔS/N) and unable to interact with the SV40 large T antigen could induce an acute cell cycle block, stable prolongation of the cell cycle in G0/G1 and G2/M phases, and suppression of the growth of tumor cells. ΔS/N showed increased affinity for E2F4, bound hyperphosphorylated forms of E2F4, and induced its nuclear compartmentalization. The ability of ΔS/N to form complexes with E2F4 on DNA was associated with an increased formation of “free” E2F4 and trans-suppression of a specific reporter through preferential binding to E2F4, but not to E2F1. Stable expression of ΔS/N in multipotent fibroblasts promoted early muscle commitment. It was assumed that a mutation in the T antigen-binding region increases pRb affinity for E2F4 combined with activation of muscle differentiation. [ABSTRACT FROM AUTHOR]

The retinoblastoma protein pRB suppresses tumorigenesis largely through regulation of the E2F transcription factors. E2F4, the most abundant E2F protein, is thought to act in cooperation with pRB to restrain cell proliferation. In this study, we analyse how loss of E2f4 affects the tumorigenicity of pRB-deficient tissues. As Rb−/−;E2f4−/− germline mice die in utero, we generated Rb−/−;E2f4−/− chimeric animals to allow examination of adult tumor phenotypes. We found that loss of E2f4 had a differential effect on known Rb-associated neuroendocrine tumors. It did not affect thyroid and adrenal glands tumors but partially suppressed lung neuroendocrine hyperplasia. The most striking effect was in the pituitary where E2F4 loss delayed the development, and reduced the incidence, of Rb mutant tumors. This tumor suppression increased the longevity of the Rb−/−;E2f4−/− chimeric animals allowing us to identify novel tumor types. We observed ganglionic neuroendocrine neoplasms, lesions not associated earlier with mutation of either Rb or E2f4. Moreover, a subset of the Rb−/−;E2f4−/− chimeras developed either low- or high-grade carcinomas in the urothelium transitional epithelium supporting a key role for Rb in bladder cancer.Oncogene (2009) 28, 500–508; doi:10.1038/onc.2008.406; published online 10 November 2008 [ABSTRACT FROM AUTHOR]