Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions.However,the importance and underlying mechanisms of these micro...Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions.However,the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely been studied.Here,we show that the novel protein TPM3P9,encoded by the lncRNA tropomyosin 3 pseudogene 9,exhibits oncogenic activity in clear cell renal cell carcinoma(ccRCC)by enhancing oncogenic RNA splicing.Overexpression of TPM3P9 promotes cell proliferation and tumor growth.Mechanistically,TPM3P9 binds to the RRM1 domain of the splicing factor RBM4 to inhibit RBM4-mediated exon skipping in the transcription factor TCF7L2.This results in increased expression of the oncogenic splice variant TCF7L2-L,which activates NF-κB signaling via its interaction with SAM68 to transcriptionally induce RELB expression.From a clinical perspective,TPM3P9 expression is upregulated in cancer tissues and is significantly correlated with the expression of TCF7L2-L and RELB.High TPM3P9 expression or low RBM4 expression is associated with poor survival in patients with ccRCC.Collectively,our findings functionally and clinically characterize the“noncoding RNA”-derived microprotein TPM3P9 and thus identify potential prognostic and therapeutic factors in renal cancer.展开更多
The roles of concealed microproteins encoded by long noncoding RNAs(lncRNAs)are gradually being exposed,but their functions in tumorigenesis are still largely unclear.Here,we identify and characterize a conserved 99-a...The roles of concealed microproteins encoded by long noncoding RNAs(lncRNAs)are gradually being exposed,but their functions in tumorigenesis are still largely unclear.Here,we identify and characterize a conserved 99-amino acid microprotein named KRASIM that is encoded by the putative lncRNA NCBP2-AS2.KRASIM is differentially expressed in normal hepatocytes and hepatocellular carcinoma(HCC)cells and can suppress HCC cell growth and proliferation.Mechanistically,KRASIM interacts and colocalizes with the KRAS protein in the cytoplasm of human HuH-7 hepatoma cells.More importantly,the overexpression of KRASIM decreases the KRAS protein level,leading to the inhibition of ERK signaling activity in HCC cells.These results demonstrate a novel microprotein repressor of the KRAS pathway for the first time and provide new insights into the regulatory mechanisms of oncogenic signaling and HCC therapy.展开更多
Proteins usually assemble oligomers or high-order complexes to increase their efficiency and specificity in biological processes.The dynamic equilibrium of complex formation and disruption imposes reversible regulatio...Proteins usually assemble oligomers or high-order complexes to increase their efficiency and specificity in biological processes.The dynamic equilibrium of complex formation and disruption imposes reversible regulation of protein function.MicroProteins are small,single-domain proteins that directly bind target protein complexes and disrupt their assembly.Growing evidence shows that microProteins are efficient regulators of protein activity at the post-translational level.In the last few decades,thousands of plant microProteins have been predicted by computational approaches,but only a few have been experimentally validated.Recent studies highlighted the mechanistic working modes of newly-identified microProteins in Arabidopsis and other plant species.Here,we review characterized microProteins,including their biological roles,regulatory targets,and modes of action.In particular,we focus on microProtein-directed allosteric modulation of key components in light signaling pathways,and we summarize the biogenesis and evolutionary trajectory of known microProteins in plants.Understanding the regulatory mechanisms of microProteins is an important step towards potential utilization of microProteins as versatile biotechnological tools in crop bioengineering.展开更多
Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention,without significant off-target effects.Although reprogramming multioncoprotein interac...Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention,without significant off-target effects.Although reprogramming multioncoprotein interactions in a single signaling pathway axis has been shown to achieve sustained efficacy,there are several challenges that limit its clinical application.Herein,we transformed the mouse double minute 2 homolog(MDM2)-heat shock cognate protein 70(HSC70)axis,a tumor-promoting pathway,into an activator of anti-tumor immunity using the Path-editor,an artificial selenoprotein.Once it enters the cell,Path-editor decomposes into PMI and PPI peptides:PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression,while PPI binds to HSC70,enabling its ability to selectively degrade the programmed cell death ligand 1(PD-L1).As a proof of concept,we tested its performance in microsatellite-stable(MSS)colorectal cancer,which typically displays limited responsiveness to immunotherapy.The results indicated that Path-editor effectively attenuated PD-L1 expression and reversed immune evasion in both CT26 allografts and humanized patient-derived tumor xenograft(PDX)models,thereby inhibiting tumor progression with high biosafety.Therefore,this paper introduces Path-editor as a paradigm for reprogramming oncogenic multi-protein pathways,utilizing selenium-assisted approach to achieve the rapid design of tumor-specific pathway editors.This strategy is expected to reverse immune escape in MSS colorectal cancer and treat difficult malignancies.展开更多
基金supported by the National Key Research and Development Program of China(2022YFA1304604,2020YFE0202200)the Fundamental Research Funds for the Central Universities(21624109)+3 种基金the Young Scientists Fund of the National Natural Science Foundation of China(82303050)the Guangdong Natural Science Foundation(2022A1515012388)the Natural Science Foundation of Guangdong Province(2023A1515011901)the Guangdong Basic and Applied Basic Research Foundation(2022A1515111106).
文摘Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions.However,the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely been studied.Here,we show that the novel protein TPM3P9,encoded by the lncRNA tropomyosin 3 pseudogene 9,exhibits oncogenic activity in clear cell renal cell carcinoma(ccRCC)by enhancing oncogenic RNA splicing.Overexpression of TPM3P9 promotes cell proliferation and tumor growth.Mechanistically,TPM3P9 binds to the RRM1 domain of the splicing factor RBM4 to inhibit RBM4-mediated exon skipping in the transcription factor TCF7L2.This results in increased expression of the oncogenic splice variant TCF7L2-L,which activates NF-κB signaling via its interaction with SAM68 to transcriptionally induce RELB expression.From a clinical perspective,TPM3P9 expression is upregulated in cancer tissues and is significantly correlated with the expression of TCF7L2-L and RELB.High TPM3P9 expression or low RBM4 expression is associated with poor survival in patients with ccRCC.Collectively,our findings functionally and clinically characterize the“noncoding RNA”-derived microprotein TPM3P9 and thus identify potential prognostic and therapeutic factors in renal cancer.
基金This work was supported by the National Key Research and Development Program of China(2017YFA0504400)the National Natural Science Foundation of China(31370791,31671349,31770879)+2 种基金Fundamental Research Funds for the Central Universities(14lgjc18)This research was supported in part by the Guangdong Province Key Laboratory of Computational Science(13lgjc05)the Guangdong Province Computational Science Innovative Research Team(14lgjc18).
文摘The roles of concealed microproteins encoded by long noncoding RNAs(lncRNAs)are gradually being exposed,but their functions in tumorigenesis are still largely unclear.Here,we identify and characterize a conserved 99-amino acid microprotein named KRASIM that is encoded by the putative lncRNA NCBP2-AS2.KRASIM is differentially expressed in normal hepatocytes and hepatocellular carcinoma(HCC)cells and can suppress HCC cell growth and proliferation.Mechanistically,KRASIM interacts and colocalizes with the KRAS protein in the cytoplasm of human HuH-7 hepatoma cells.More importantly,the overexpression of KRASIM decreases the KRAS protein level,leading to the inhibition of ERK signaling activity in HCC cells.These results demonstrate a novel microprotein repressor of the KRAS pathway for the first time and provide new insights into the regulatory mechanisms of oncogenic signaling and HCC therapy.
基金supported by the National Natural Science Foundation of China(31770208)the Support Project of High-Level Teachers in Beijing Municipal Universities in the Period of 13th Five-Year Plan(CIT&TCD20190331).
文摘Proteins usually assemble oligomers or high-order complexes to increase their efficiency and specificity in biological processes.The dynamic equilibrium of complex formation and disruption imposes reversible regulation of protein function.MicroProteins are small,single-domain proteins that directly bind target protein complexes and disrupt their assembly.Growing evidence shows that microProteins are efficient regulators of protein activity at the post-translational level.In the last few decades,thousands of plant microProteins have been predicted by computational approaches,but only a few have been experimentally validated.Recent studies highlighted the mechanistic working modes of newly-identified microProteins in Arabidopsis and other plant species.Here,we review characterized microProteins,including their biological roles,regulatory targets,and modes of action.In particular,we focus on microProtein-directed allosteric modulation of key components in light signaling pathways,and we summarize the biogenesis and evolutionary trajectory of known microProteins in plants.Understanding the regulatory mechanisms of microProteins is an important step towards potential utilization of microProteins as versatile biotechnological tools in crop bioengineering.
基金supported by the National Natural Science Foundation of China(Grant No.:82272782)the Shaanxi Natural Science Foundation Research Program,China(Grant No.:2024JCYBMS-795).
文摘Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention,without significant off-target effects.Although reprogramming multioncoprotein interactions in a single signaling pathway axis has been shown to achieve sustained efficacy,there are several challenges that limit its clinical application.Herein,we transformed the mouse double minute 2 homolog(MDM2)-heat shock cognate protein 70(HSC70)axis,a tumor-promoting pathway,into an activator of anti-tumor immunity using the Path-editor,an artificial selenoprotein.Once it enters the cell,Path-editor decomposes into PMI and PPI peptides:PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression,while PPI binds to HSC70,enabling its ability to selectively degrade the programmed cell death ligand 1(PD-L1).As a proof of concept,we tested its performance in microsatellite-stable(MSS)colorectal cancer,which typically displays limited responsiveness to immunotherapy.The results indicated that Path-editor effectively attenuated PD-L1 expression and reversed immune evasion in both CT26 allografts and humanized patient-derived tumor xenograft(PDX)models,thereby inhibiting tumor progression with high biosafety.Therefore,this paper introduces Path-editor as a paradigm for reprogramming oncogenic multi-protein pathways,utilizing selenium-assisted approach to achieve the rapid design of tumor-specific pathway editors.This strategy is expected to reverse immune escape in MSS colorectal cancer and treat difficult malignancies.
