The Experts below are selected from a list of 113178 Experts worldwide ranked by ideXlab platform
Teruhisa Kawamura - One of the best experts on this subject based on the ideXlab platform.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:This paper reports that the transcription factor p53 plays a crucial role in regulating somatic Reprogramming. The authors develop an experimental protocol to reprogram somatic cells using just two factors, Oct4 and Sox2, when p53 is silenced. On the other hand, overexpression of p53 or the presence of Nutlin-3 (a p53 stabilizer) reduces Reprogramming efficiency. Expression of pluripotency factors and oncogenes can reprogram somatic cells to induced pluripotent stem cells, albeit with low frequency and a tendency to induce malignant transformation. Here, Reprogramming factors are shown to activate the p53 pathway, providing insights into Reprogramming mechanisms. Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1,2,3,4,5,6,7,8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
Juan Carlos Izpisua Belmonte - One of the best experts on this subject based on the ideXlab platform.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:This paper reports that the transcription factor p53 plays a crucial role in regulating somatic Reprogramming. The authors develop an experimental protocol to reprogram somatic cells using just two factors, Oct4 and Sox2, when p53 is silenced. On the other hand, overexpression of p53 or the presence of Nutlin-3 (a p53 stabilizer) reduces Reprogramming efficiency. Expression of pluripotency factors and oncogenes can reprogram somatic cells to induced pluripotent stem cells, albeit with low frequency and a tendency to induce malignant transformation. Here, Reprogramming factors are shown to activate the p53 pathway, providing insights into Reprogramming mechanisms. Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1,2,3,4,5,6,7,8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
Jotaro Suzuki - One of the best experts on this subject based on the ideXlab platform.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:This paper reports that the transcription factor p53 plays a crucial role in regulating somatic Reprogramming. The authors develop an experimental protocol to reprogram somatic cells using just two factors, Oct4 and Sox2, when p53 is silenced. On the other hand, overexpression of p53 or the presence of Nutlin-3 (a p53 stabilizer) reduces Reprogramming efficiency. Expression of pluripotency factors and oncogenes can reprogram somatic cells to induced pluripotent stem cells, albeit with low frequency and a tendency to induce malignant transformation. Here, Reprogramming factors are shown to activate the p53 pathway, providing insights into Reprogramming mechanisms. Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1,2,3,4,5,6,7,8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
Sergio Menendez - One of the best experts on this subject based on the ideXlab platform.
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Reprogramming Roadblocks Are System Dependent
Stem cell reports, 2015Co-Authors: Eleni Chantzoura, Sergio Menendez, Stavroula Skylaki, Shin-il Kim, Anna Johnsson, Sten Linnarsson, Knut Woltjen, Ian Chambers, Keisuke KajiAbstract:Since the first generation of induced pluripotent stem cells (iPSCs), several Reprogramming systems have been used to study its molecular mechanisms. However, the system of choice largely affects the Reprogramming efficiency, influencing our view on the mechanisms. Here, we demonstrate that Reprogramming triggered by less efficient polycistronic Reprogramming cassettes not only highlights mesenchymal-to-epithelial transition (MET) as a roadblock but also faces more severe difficulties to attain a pluripotent state even post-MET. In contrast, more efficient cassettes can reprogram both wild-type and Nanog−/− fibroblasts with comparable efficiencies, routes, and kinetics, unlike the less efficient Reprogramming systems. Moreover, we attribute a previously reported variation in the N terminus of KLF4 as a dominant factor underlying these critical differences. Our data establish that some Reprogramming roadblocks are system dependent, highlighting the need to pursue mechanistic studies with close attention to the systems to better understand Reprogramming.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:This paper reports that the transcription factor p53 plays a crucial role in regulating somatic Reprogramming. The authors develop an experimental protocol to reprogram somatic cells using just two factors, Oct4 and Sox2, when p53 is silenced. On the other hand, overexpression of p53 or the presence of Nutlin-3 (a p53 stabilizer) reduces Reprogramming efficiency. Expression of pluripotency factors and oncogenes can reprogram somatic cells to induced pluripotent stem cells, albeit with low frequency and a tendency to induce malignant transformation. Here, Reprogramming factors are shown to activate the p53 pathway, providing insights into Reprogramming mechanisms. Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1,2,3,4,5,6,7,8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
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linking the p53 tumour suppressor pathway to somatic cell Reprogramming
Nature, 2009Co-Authors: Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V Wang, Sergio Menendez, Laura Batlle Morera, Angel Raya, Geoffrey M Wahl, Juan Carlos Izpisua BelmonteAbstract:Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting Reprogramming efficiency in somatic cells. Here we show that Reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing Reprogramming-induced apoptosis in mouse fibroblasts increases Reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the Reprogramming efficiency of human somatic cells. These results provide insights into Reprogramming mechanisms and suggest new routes to more efficient Reprogramming while minimizing the use of oncogenes.
John B. Gurdon - One of the best experts on this subject based on the ideXlab platform.
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h3k4 methylation dependent memory of somatic cell identity inhibits Reprogramming and development of nuclear transfer embryos
Cell Stem Cell, 2017Co-Authors: Eva Hormanseder, John B. Gurdon, Angela Simeone, George E Allen, Charles R Bradshaw, Magdalena Figlmuller, Jerome JullienAbstract:Summary Vertebrate eggs can induce the nuclear Reprogramming of somatic cells to enable production of cloned animals. Nuclear Reprogramming is relatively inefficient, and the development of the resultant embryos is frequently compromised, in part due to the inappropriate expression of genes previously active in the donor nucleus. Here, we identify H3K4 methylation as a major epigenetic roadblock that limits transcriptional Reprogramming and efficient nuclear transfer (NT). Widespread expression of donor-cell-specific genes was observed in inappropriate cell types in NT embryos, limiting their developmental capacity. The expression of these genes in reprogrammed embryos arises from epigenetic memories of a previously active transcriptional state in donor cells that is characterized by high H3K4 methylation. Reducing H3K4 methylation had little effect on gene expression in donor cells, but it substantially improved transcriptional Reprogramming and development of NT embryos. These results show that H3K4 methylation imposes a barrier to efficient nuclear Reprogramming and suggest approaches for improving Reprogramming strategies.
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Nuclear Reprogramming
Development, 2013Co-Authors: Richard P. Halley-stott, Vincent Pasque, John B. GurdonAbstract:There is currently particular interest in the field of nuclear Reprogramming, a process by which the identity of specialised cells may be changed, typically to an embryonic-like state. Reprogramming procedures provide insight into many mechanisms of fundamental cell biology and have several promising applications, most notably in healthcare through the development of human disease models and patient-specific tissue-replacement therapies. Here, we introduce the field of nuclear Reprogramming and briefly discuss six of the procedures by which Reprogramming may be experimentally performed: nuclear transfer to eggs or oocytes, cell fusion, extract treatment, direct Reprogramming to pluripotency and transdifferentiation.
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Reprogramming and development in nuclear transfer embryos and in interspecific systems
Current Opinion in Genetics & Development, 2012Co-Authors: Patrick Narbonne, Kei Miyamoto, John B. GurdonAbstract:Nuclear transfer (NT) remains the most effective method to reprogram somatic cells to totipotency. Somatic cell nuclear transfer (SCNT) efficiency however remains low, but recurrent problems occurring in partially reprogrammed cloned embryos have recently been identified and some remedied. In particular, the trophectoderm has been identified as a lineage whose Reprogramming success has a large influence on SCNT embryo development. Several interspecific hybrid and cybrid Reprogramming systems have been developed as they offer various technical advantages and potential applications, and together with SCNT, they have led to the identification of a series of Reprogramming events and responsible Reprogramming factors. Interspecific incompatibilities hinder full exploitation of cross-species Reprogramming systems, yet recent findings suggest that these may not constitute insurmountable obstacles.
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epigenetic factors influencing resistance to nuclear Reprogramming
Trends in Genetics, 2011Co-Authors: Vincent Pasque, Richard P Halleystott, Jerome Jullien, Kei Miyamoto, John B. GurdonAbstract:Patient-specific somatic cell Reprogramming is likely to have a large impact on medicine by providing a source of cells for disease modelling and regenerative medicine. Several strategies can be used to reprogram cells, yet they are generally characterised by a low Reprogramming efficiency, reflecting the remarkable stability of the differentiated state. Transcription factors, chromatin modifications, and noncoding RNAs can increase the efficiency of Reprogramming. However, the success of nuclear Reprogramming is limited by epigenetic mechanisms that stabilise the state of gene expression in somatic cells and thereby resist efficient Reprogramming. We review here the factors that influence Reprogramming efficiency, especially those that restrict the natural Reprogramming mechanisms of eggs and oocytes. We see this as a step towards understanding the mechanisms by which nuclear Reprogramming takes place.
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Efficiencies and Mechanisms of Nuclear Reprogramming
Cold Spring Harbor Symposia on Quantitative Biology, 2010Co-Authors: Vincent Pasque, Kei Miyamoto, John B. GurdonAbstract:The differentiated state of somatic cells is highly stable, but it can be experimentally reversed. The resulting cells can then be redirected into many different pathways. Nuclear Reprogramming has been achieved by nuclear transfer to eggs, cell fusion, and overexpression of transcription factors. The mechanisms of nuclear Reprogramming are not understood, but some insight into them is provided by comparing the efficiencies of different Reprogramming strategies. Here, we compare these efficiencies by describing the frequency and rapidity with which Reprogramming is induced and by the proportion of cells and level of expression in which Reprogramming is achieved. We comment on the mechanisms that lead to successful somatic-cell Reprogramming and on those that resist in helping to maintain the differentiated state of somatic cells.
