Dopaminergic(DA)neuron-like cells obtained through direct reprogramming of primary human fibroblasts offer exciting opportunities for treatment of Parkinson’s disease.A significant obstacle is the low efficiency of c...Dopaminergic(DA)neuron-like cells obtained through direct reprogramming of primary human fibroblasts offer exciting opportunities for treatment of Parkinson’s disease.A significant obstacle is the low efficiency of conversion during the reprogramming process.Here,we demonstrate that the suppression of p53 significantly enhances the efficiency of transcription factor-mediated conversion of human fibroblasts into functional dopaminergic neurons.In particular,blocking p53 activity using a dominant-negative p53(p53-DN)in IMR90 cells increases the conversion efficiency by 5–20 fold.The induced DA neuron-like cells exhibit dopamine neuron-specific gene expression,significant dopamine uptake and production capacities,and enables symptomatic relief in a rat Parkinson’s disease model.Taken together,our findings suggest that p53 is a critical barrier in direct reprogramming of fibroblast into dopaminergic neurons.展开更多
The tumor suppressor p53 pathway, whose alterations are highly associated with all types of human cancers, plays an essential role in preventingtumor development and progression mostly through its downstream target ge...The tumor suppressor p53 pathway, whose alterations are highly associated with all types of human cancers, plays an essential role in preventingtumor development and progression mostly through its downstream target genes. Over the last decade, a growing list of p53 microRNA （miRNA） targets has been identified as additional downstream players of this pathway. Further studies ofthese miRNAs have revealed their more complicated regulations and functions in executing and/or regulating p53 activity. Here, we review the p53 miRNA targets identified thus far, and discuss how they fine-tune p53 stress responses, mediate the crosstalk between p53 and other signaling pathways, and expand the role of p53 in other human diseases in addition to cancers.展开更多
基金supported in part by grants from the US National Institutes of Health(CA131408,CA136748,CA155270,ES024015)to Li Chuan-Yuan
文摘Dopaminergic(DA)neuron-like cells obtained through direct reprogramming of primary human fibroblasts offer exciting opportunities for treatment of Parkinson’s disease.A significant obstacle is the low efficiency of conversion during the reprogramming process.Here,we demonstrate that the suppression of p53 significantly enhances the efficiency of transcription factor-mediated conversion of human fibroblasts into functional dopaminergic neurons.In particular,blocking p53 activity using a dominant-negative p53(p53-DN)in IMR90 cells increases the conversion efficiency by 5–20 fold.The induced DA neuron-like cells exhibit dopamine neuron-specific gene expression,significant dopamine uptake and production capacities,and enables symptomatic relief in a rat Parkinson’s disease model.Taken together,our findings suggest that p53 is a critical barrier in direct reprogramming of fibroblast into dopaminergic neurons.
文摘The tumor suppressor p53 pathway, whose alterations are highly associated with all types of human cancers, plays an essential role in preventingtumor development and progression mostly through its downstream target genes. Over the last decade, a growing list of p53 microRNA （miRNA） targets has been identified as additional downstream players of this pathway. Further studies ofthese miRNAs have revealed their more complicated regulations and functions in executing and/or regulating p53 activity. Here, we review the p53 miRNA targets identified thus far, and discuss how they fine-tune p53 stress responses, mediate the crosstalk between p53 and other signaling pathways, and expand the role of p53 in other human diseases in addition to cancers.
