Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation,their ribosomeindependent functions have also been greatly appreciated.Over the past decade,more than a ...Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation,their ribosomeindependent functions have also been greatly appreciated.Over the past decade,more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress.In addition,these ribosomal proteins are involved in various physiological and pathological processes.This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins,as well as the ribosome-independent functions of ribosomal proteins in tumorigenesis,immune signaling,and development.Wealso propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics.展开更多
5q-syndrome is a distinct form of myelodysplastic syndrome（MDS） where a deletion on chromosome 5 is the underlying cause.MDS is characterized by bone marrow failures,including macrocytic anemia.Genetic mapping and s...5q-syndrome is a distinct form of myelodysplastic syndrome（MDS） where a deletion on chromosome 5 is the underlying cause.MDS is characterized by bone marrow failures,including macrocytic anemia.Genetic mapping and studies using various models support the notion that ribosomal protein S14（RPS14） is the candidate gene for the erythroid failure.Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis,similar to what is observed with other ribosomal proteins.However,due to the higher risk for cancer development in patients with ribosome deficiency,targeting the p53 pathway is not a viable treatment option.To better understand the pathology of RPS14 deficiency in 5q-deletion,we generated a zebrafish model harboring a mutation in the RPS14 gene.This model mirrors the anemic phenotype seen in 5q-syndrome.Moreover,the anemia is due to a late-stage erythropoietic defect,where the erythropoietic defect is initially p53-independent and then becomes p53-dependent.Finally,we demonstrate the versatility of this model to test various pharmacological agents,such as RAP-011,L-leucine,and dexamethasone in order to identify molecules that can reverse the anemic phenotype.展开更多
基金H.L.was supported by NIH-NCI grants CA095441 and CA172468the Reynolds and Ryan Families chair fund.
文摘Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation,their ribosomeindependent functions have also been greatly appreciated.Over the past decade,more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress.In addition,these ribosomal proteins are involved in various physiological and pathological processes.This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins,as well as the ribosome-independent functions of ribosomal proteins in tumorigenesis,immune signaling,and development.Wealso propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics.
基金supported by Celgene(Nov022011)National Institutes of Health(R56 DK107286)
文摘5q-syndrome is a distinct form of myelodysplastic syndrome（MDS） where a deletion on chromosome 5 is the underlying cause.MDS is characterized by bone marrow failures,including macrocytic anemia.Genetic mapping and studies using various models support the notion that ribosomal protein S14（RPS14） is the candidate gene for the erythroid failure.Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis,similar to what is observed with other ribosomal proteins.However,due to the higher risk for cancer development in patients with ribosome deficiency,targeting the p53 pathway is not a viable treatment option.To better understand the pathology of RPS14 deficiency in 5q-deletion,we generated a zebrafish model harboring a mutation in the RPS14 gene.This model mirrors the anemic phenotype seen in 5q-syndrome.Moreover,the anemia is due to a late-stage erythropoietic defect,where the erythropoietic defect is initially p53-independent and then becomes p53-dependent.Finally,we demonstrate the versatility of this model to test various pharmacological agents,such as RAP-011,L-leucine,and dexamethasone in order to identify molecules that can reverse the anemic phenotype.
