c-Myc Is Dispensable for Direct Reprogramming of Mouse Fibroblasts

Cell stem cell (Impact Factor: 22.27). 02/2008; 2(1):10-2. DOI: 10.1016/j.stem.2007.12.001
Source: PubMed


Retroviral transduction of the four transcription factors Oct4, Sox2, Klf4, and c-Myc has been shown to initiate a reprogramming process that results in the transformation of mouse fibroblasts into embryonic stem (ES)-like cells designated as induced pluripotent stem (iPS) cells (Maherali et al., 2007, Meissner et al., 2007, Okita et al., 2007, Takahashi and Yamanaka, 2006 and Wernig et al., 2007). The promise of somatic reprogramming is the possibility to generate pluripotent stem cells that are patient specific and can be used as a unique source for autologous cell types for transplantation therapy (Jaenisch, 2004 and Yamanaka, 2007). Many iPS cell-derived animals develop tumors due to the reactivation of the c-Myc virus (Okita et al., 2007), and this represents a major safety concern if we want to translate this approach to humans. It is thus of great importance to achieve reprogramming without this particular oncogene in the future. Here we show that fibroblasts can be reprogrammed to a pluripotent state by Oct4, Sox2, and Klf4 in the absence of c-Myc.

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    • "Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share some similarities to cancer cells, including the capacity to bypass senescence and form tumors upon transplantation (Goding et al., 2014). Accordingly, some genes often associated with cancer, such as Myc (Nakagawa et al., 2008; Wernig et al., 2008), p53 (Krizhanovsky and Lowe, 2009), and telomerase (Batista et al., 2011; Park et al., 2008), have been implicated in cellular reprogramming. Additionally, two reprogramming factors, Oct4 and Sox2, can be oncogenic in some cellular contexts (Hochedlinger et al., 2005; Lu et al., 2010; Rudin et al., 2012; Sarkar and Hochedlinger, 2013). "
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    ABSTRACT: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
    Cell Stem Cell 01/2015; 16(1). DOI:10.1016/j.stem.2014.10.019 · 22.27 Impact Factor
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    • "Six common nuclear reprogramming factors (OCT4, SOX2, KLF4, C-MYC, NANOG, and LIN28) are extensively used for generating iPS cells. However, it is possible to reprogram somatic cells with three transcription factors OCT4, SOX2 and KLF4, excluding c-MYC15 as it is naturally oncogenic (7,8). Although, the efficiency is reported to be low (7). "
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    ABSTRACT: Research related to induce pluripotent stem (iPS) cell generation has increased rapidly in recent years. Six transcription factors, namely OCT4, SOX2, C-MYC, KLF4, NANOG, and LIN28 have been widely used for iPS cell generation. As there is a lack of data on intra- and inter-networking among these six different transcription factors, the objective of this study is to analyze the intra- and inter-networks between them using bioinformatics. In this computational biology study, we used AminoNet, MATLAB to examine networking between the six different transcription factors. The directed network was constructed using MATLAB programming and the distance between nodes was estimated using a phylogram. The protein-protein interactions between the nuclear reprogramming factors was performed using the software STRING. The relationship between C-MYC and NANOG was depicted using a phylogenetic tree and the sequence analysis showed OCT4, C-MYC, NANOG, and SOX2 together share a common evolutionary origin. This study has shown an innovative rapid method for the analysis of intra and inter-networking among nuclear reprogramming factors. Data presented may aid researchers to understand the complex regulatory networks involving iPS cell generation.
    Cell Journal 12/2014; 15(4):332-339. · 1.11 Impact Factor
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    • "Factor-mediated reprogramming, the process by which overexpression of a defined set of transcription factors converts one cell type into another, has important implications for regenerative medicine and demonstrates the power that transcription factors have as cell fate determinants (Jaenisch and Young, 2008). This has been shown for pluripotent stem cells, where three transcription factors (Oct4, Sox2, and Klf4) are sufficient to induce any cell type to become induced pluripotent stem cells (iPSCs) that are transcriptionally, epigenetically, and functionally indistinguishable from embryonic stem cells (ESCs) (Takahashi and Yamanaka, 2006; Wernig et al., 2008a). "
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    ABSTRACT: Overexpression of transcription factors has been used to directly reprogram somatic cells into a range of other differentiated cell types, including multipotent neural stem cells (NSCs), that can be used to generate neurons and glia. However, the ability to maintain the NSC state independent of the inducing factors and the identity of the somatic donor cells remain two important unresolved issues in transdifferentiation. Here we used transduction of doxycycline-inducible transcription factors to generate stable tripotent NSCs. The induced NSCs (iNSCs) maintained their characteristics in the absence of exogenous factor expression and were transcriptionally, epigenetically, and functionally similar to primary brain-derived NSCs. Importantly, we also generated tripotent iNSCs from multiple adult cell types, including mature liver and B cells. Our results show that self-maintaining proliferative neural cells can be induced from nonectodermal cells by expressing specific combinations of transcription factors. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 11/2014; 3(6). DOI:10.1016/j.stemcr.2014.10.001 · 5.37 Impact Factor
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