Recent advancements in the production,modification,and cellular delivery of RNA molecules facilitated the expansion of RNAbased therapeutics.The increasing understanding of RNA biology initiated a corresponding growth...Recent advancements in the production,modification,and cellular delivery of RNA molecules facilitated the expansion of RNAbased therapeutics.The increasing understanding of RNA biology initiated a corresponding growth in RNA therapeutics.In this review,the general concepts of five classes of RNA-based therapeutics,including RNA interference-based therapies,antisense oligonucleotides,small activating RNA therapies,circular RNA therapies,and messenger RNA-based therapeutics,will be discussed.Moreover,we also provide an overview of RNA-based therapeutics that have already received regulatory approval or are currently being evaluated in clinical trials,along with challenges faced by these technologies.RNA-based drugs demonstrated positive clinical trial results and have the ability to address previously“undruggable”targets,which delivers great promise as a disruptive therapeutic technology to fulfill its full clinical potentiality.展开更多
NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of protei...NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of proteins.The roles of PPs regulating NF-kappaB activities are poorly understood.Here we describe an RNAi-based screen to identify the PPs that involve in regulating NFkappaB signaling.Thirty-four candidate PPs siRNAs were synthesized and primarily screened by NF-kappaB reporter gene assay in HeLa cells.PHLPP,one of the protein phosphatase type 2C family members(PP2C),was identified as a positive regulator of NF-kappaB signaling.Knock-down of PHLPP dramatically attenuated TNFα-stimulated NF-kappaB transcriptional activation.Knockdown of PHLPP led to enhancement of NF-kappaB/p65 nuclear import and retention,but decreased TNFα-induced phosphorylation at Ser276 on p65.This critical phosphorylation was also drastically reduced by knock-down of PKCalpha and Akt1,two important serine/threonine kinases dephosphorylated by PHLPP.The results together suggest that PHLPP-Akt-PKC may represent an important signaling loop that activates NF-kappaB/p65 signaling through critical serine phosphorylation.展开更多
文摘Recent advancements in the production,modification,and cellular delivery of RNA molecules facilitated the expansion of RNAbased therapeutics.The increasing understanding of RNA biology initiated a corresponding growth in RNA therapeutics.In this review,the general concepts of five classes of RNA-based therapeutics,including RNA interference-based therapies,antisense oligonucleotides,small activating RNA therapies,circular RNA therapies,and messenger RNA-based therapeutics,will be discussed.Moreover,we also provide an overview of RNA-based therapeutics that have already received regulatory approval or are currently being evaluated in clinical trials,along with challenges faced by these technologies.RNA-based drugs demonstrated positive clinical trial results and have the ability to address previously“undruggable”targets,which delivers great promise as a disruptive therapeutic technology to fulfill its full clinical potentiality.
基金This research was supported by the National High Technology Research and Development Program of China(863 Program)(No.2006AA02Z191),the Bureau of Science and Technology of Guangzhou,China(No.2007Z1-E4041)Guangzhou Economic&Technological Development District(GETDD S&T Project)(2007G-P029).
文摘NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of proteins.The roles of PPs regulating NF-kappaB activities are poorly understood.Here we describe an RNAi-based screen to identify the PPs that involve in regulating NFkappaB signaling.Thirty-four candidate PPs siRNAs were synthesized and primarily screened by NF-kappaB reporter gene assay in HeLa cells.PHLPP,one of the protein phosphatase type 2C family members(PP2C),was identified as a positive regulator of NF-kappaB signaling.Knock-down of PHLPP dramatically attenuated TNFα-stimulated NF-kappaB transcriptional activation.Knockdown of PHLPP led to enhancement of NF-kappaB/p65 nuclear import and retention,but decreased TNFα-induced phosphorylation at Ser276 on p65.This critical phosphorylation was also drastically reduced by knock-down of PKCalpha and Akt1,two important serine/threonine kinases dephosphorylated by PHLPP.The results together suggest that PHLPP-Akt-PKC may represent an important signaling loop that activates NF-kappaB/p65 signaling through critical serine phosphorylation.
