Article

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

ABSTRACT

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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    • "During reprogramming, Oct4, Sox2 and Klf4 act as the core pluripotency network which is generally believed to be crucial for specifying cell fate change, whereas simply assists OSK to access target sites for amplifying transcriptional outputs [81]. Indeed, few differences are present between the two types of iPSCs (OSKM-induced and OSK-induced) in terms of analyses of phenotype, molecular biology, cytochemistry and non-programmed differentiation [80] [82] [83]. However, marked differences were evident when the two types of iPSCs were examined for germline contribution. "
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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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    • "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.
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