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1.
Int J Mol Sci ; 24(22)2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-38003508

RESUMO

FMRP is a multifunctional protein encoded by the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1). The inactivation of the FMR1 gene results in fragile X syndrome (FXS), a serious neurodevelopmental disorder. FMRP deficiency causes abnormal neurite outgrowth, which is likely to lead to abnormal learning and memory capabilities. However, the mechanism of FMRP in modulating neuronal development remains unknown. We found that FMRP enhances the translation of 4EBP2, a neuron-specific form of 4EBPs that inactivates eIF4E by inhibiting the interaction between eIF4E and eIF4G. Depletion of 4EBP2 results in abnormal neurite outgrowth. Moreover, the impairment of neurite outgrowth upon FMRP depletion was overcome by the ectopic expression of 4EBP2. These results suggest that FMRP controls neuronal development by enhancing 4EBP2 expression at the translational level. In addition, treatment with 4EGI-1, a chemical that blocks eIF4E activity, restored neurite length in FMRP-depleted and 4EBP2-depleted cells. In conclusion, we discovered that 4EBP2 functions as a key downstream regulator of FMRP activity in neuronal development and that FMRP represses eIF4E activity by enhancing 4EBP2 translation.


Assuntos
Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Humanos , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Neurônios/metabolismo , Síndrome do Cromossomo X Frágil/genética , Diferenciação Celular/genética
2.
Cell Mol Life Sci ; 77(22): 4693-4708, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32030451

RESUMO

During mitosis, translation of most mRNAs is strongly repressed; none of the several explanatory hypotheses suggested can fully explain the molecular basis of this phenomenon. Here we report that cyclin-dependent CDK11/p58-a serine/threonine kinase abundantly expressed during M phase-represses overall translation by phosphorylating a subunit (eIF3F) of the translation factor eIF3 complex that is essential for translation initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed cap-dependent translation, and knockdown of CDK11/p58 nullified the translational repression during M phase. We identified the phosphorylation sites in eIF3F responsible for M phase-specific translational repression by CDK11/p58. Alanine substitutions of CDK11/p58 target sites in eIF3F nullified its effects on cell cycle-dependent translational regulation. The mechanism of translational regulation by the M phase-specific kinase, CDK11/p58, has deep evolutionary roots considering the conservation of CDK11 and its target sites on eIF3F from C. elegans to humans.


Assuntos
Quinases Ciclina-Dependentes/genética , Mitose/genética , Biossíntese de Proteínas/genética , Proteínas Serina-Treonina Quinases/genética , Análogos de Capuz de RNA/genética , Divisão Celular/genética , Linhagem Celular Tumoral , Fator de Iniciação 3 em Eucariotos/genética , Células HeLa , Humanos , Fosforilação/genética , RNA Mensageiro/genética , Transdução de Sinais/genética
3.
RNA Biol ; 14(3): 370-377, 2017 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-28095120

RESUMO

A recent study revealed that poly(A)-binding protein (PABP) bound to poly(A) RNA exhibits a sharply bent configuration at the linker region between RNA-recognition motif 2 (RRM2) and RRM3, whereas free PABP exhibits a highly flexible linear configuration. However, the physiological role of the bent structure of mRNA-bound PABP remains unknown. We investigated a role of the bent structure of PABP by constructing a PABP variant that fails to form the poly(A)-dependent bent structure but maintains its poly(A)-binding activity. We found that the bent structure of PABP/poly(A) complex is required for PABP's efficient interaction with eIF4G and eIF4G/eIF4E complex. Moreover, the mutant PABP had compromised translation activation function and failed to augment the formation of 80S translation initiation complex in an in vitro translation system. These results suggest that the bent conformation of PABP, which is induced by the interaction with 3' poly(A) tail, mediates poly(A)-dependent translation by facilitating the interaction with eIF4G and the eIF4G/eIF4E complex. The preferential binding of the eIF4G/eIF4E complex to the bent PABP/poly(A) complex seems to be a mechanism discriminating the mRNA-bound PABPs participating in translation from the idling mRNA-unbound PABPs.


Assuntos
Proteínas de Ligação a Poli(A)/química , Proteínas de Ligação a Poli(A)/metabolismo , Biossíntese de Proteínas , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Iniciação Eucariótico 4G/metabolismo , Humanos , Complexos Multiproteicos/metabolismo , Mutação , Proteínas de Ligação a Poli(A)/genética , Ligação Proteica , Ribossomos/metabolismo , Relação Estrutura-Atividade
4.
Nucleic Acids Res ; 45(1): 296-310, 2017 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-27899592

RESUMO

c-Src, a non-receptor protein tyrosine kinase, activates NF-κB and STAT3, which in turn triggers the transcription of anti-apoptosis- and cell cycle-related genes. c-Src protein regulates cell proliferation, cell motility and programmed cell death. And the elevated level of activated c-Src protein is related with solid tumor generation. Translation of c-Src mRNA is directed by an IRES element which mediates persistent translation under stress conditions when translation of most mRNAs is inhibited by a phosphorylation of the alpha subunit of eIF2 carrying the initiator tRNA (tRNAi) to 40S ribosomal subunit under normal conditions. The molecular basis of the stress-resistant translation of c-Src mRNA remained to be elucidated. Here, we report that eIF2A, an alternative tRNAi carrier, is responsible for the stress-resistant translation of c-Src mRNA. eIF2A facilitates tRNAi loading onto the 40S ribosomal subunit in a c-Src mRNA-dependent manner. And a direct interaction between eIF2A and a stem-loop structure (SL I) in the c-Src IRES is required for the c-Src IRES-dependent translation under stress conditions but not under normal conditions. Finally, we showed that the eIF2A-dependent translation of c-Src mRNA plays a pivotal role in cell proliferation under stress conditions.


Assuntos
Fator de Iniciação 2 em Eucariotos/genética , Hepatócitos/metabolismo , Biossíntese de Proteínas , RNA de Transferência de Metionina/genética , RNA/genética , Quinases da Família src/genética , Biotinilação , Proteína Tirosina Quinase CSK , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Conformação de Ácido Nucleico , Fosforilação , RNA/metabolismo , RNA de Transferência de Metionina/metabolismo , Elementos de Resposta , Subunidades Ribossômicas Menores de Eucariotos/química , Subunidades Ribossômicas Menores de Eucariotos/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Estresse Fisiológico , Tunicamicina/farmacologia , Quinases da Família src/metabolismo
5.
PLoS One ; 8(2): e55725, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23409027

RESUMO

MicroRNAs (miRNAs) are small noncoding RNAs that mediate post-transcriptional gene silencing by binding to complementary target mRNAs and recruiting the miRNA-containing ribonucleoprotein complexes to the mRNAs. However, the molecular basis of this silencing is unclear. Here, we show that human Ago2 associates with the cap-binding protein complex and this association is mediated by human eIF4GI, a scaffold protein required for the translation initiation. Using a cap photo-crosslinking method, we show that Ago2 closely associates with the cap structure. Taken together, these data suggest that eIF4GI participates in the miRNA-mediated post-transcriptional gene silencing by promoting the association of Ago2 with the cap-binding complex.


Assuntos
Fator de Iniciação Eucariótico 4G/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , Proteínas Argonautas/metabolismo , Linhagem Celular , Ordem dos Genes , Humanos , MicroRNAs/metabolismo , Complexo Proteico Nuclear de Ligação ao Cap/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Capuzes de RNA/metabolismo
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