Distinct expression patterns of the subunits of the CCR4-NOT deadenylase complex during neural development
ABSTRACT The stability of mRNA influences the dynamics of gene expression. The mammalian CCR4-NOT complex is associated with deadenylase activity, which shortens the mRNA poly(A) tail and thereby contributes to destabilization of mRNAs. The complex consists of at least nine subunits and predominantly forms a 2.0MDa protein complex in HeLa cells. Accumulating evidence suggests that the CCR4-NOT complex is involved in cell growth and survival; however, the regulatory mechanisms of its biological activity remain obscure. Here, we analyzed the expression levels of the subunits of the CCR4-NOT complex in various mouse tissues and found that they showed distinct expression patterns. CNOT6, 6L, 7, and 10 were expressed nearly ubiquitously, whereas others were expressed in tissue-specific manners, such as those displaying especially high expression in the brain. Furthermore, CNOT2, 3, 6, and 8 were rapidly downregulated during differentiation of neural stem cells. These findings suggest that subunit composition of the CCR4-NOT complex differs among tissues and is altered during neural development, thereby imparting an additional layer of specificity in the control of gene expression.
- SourceAvailable from: Masahiro Morita
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- "The role of each subunit in the complex is also far from clear. The subunits of the CCR4-NOT complex show distinct tissue distributions (Chen et al., 2011), suggesting that the composition of the CCR4-NOT complex differs among tissues, which may reflect tissue-specific functions of this complex. Some subunits are thought to participate in transcriptional regulation. "
ABSTRACT: The human CCR4-NOT deadenylase complex consists of at least nine enzymatic and non-enzymatic subunits. Accumulating evidence suggests that the non-enzymatic subunits are involved in the regulation of mRNA deadenylation, although their precise roles remain to be established. In this study, we addressed the function of the CNOT1 subunit by depleting its expression in HeLa cells. Flow cytometric analysis revealed that the sub G(1) fraction was increased in CNOT1-depleted cells. Virtually, the same level of the sub G1 fraction was seen when cells were treated with a mixture of siRNAs targeted against all enzymatic subunits, suggesting that CNOT1 depletion induces apoptosis by destroying the CCR4-NOT-associated deadenylase activity. Further analysis revealed that CNOT1 depletion leads to a reduction in the amount of other CCR4-NOT subunits. Importantly, the specific activity of the CNOT6L immunoprecipitates-associated deadenylase from CNOT1-depleted cells was less than that from control cells. The formation of P-bodies, where mRNA decay is reported to take place, was largely suppressed in CNOT1-depleted cells. Therefore, CNOT1 has an important role in exhibiting enzymatic activity of the CCR4-NOT complex, and thus is critical in control of mRNA deadenylation and mRNA decay. We further showed that CNOT1 depletion enhanced CHOP mRNA levels and activated caspase-4, which is associated with endoplasmic reticulum ER stress-induced apoptosis. Taken together, CNOT1 depletion structurally and functionally deteriorates the CCR4-NOTcomplex and induces stabilization of mRNAs, which results in the increment of translation causing ER stress-mediated apoptosis. We conclude that CNOT1 contributes to cell viability by securing the activity of the CCR4-NOT deadenylase.Protein & Cell 09/2011; 2(9):755-63. DOI:10.1007/s13238-011-1092-4 · 2.85 Impact Factor
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ABSTRACT: A idéia de "pós-modernismo" surgiu pela primeira vez no mundo hispânico, na década de 1930, uma geração antes de seu aparecimento na Inglaterra ou nos EUA. Perry Anderson, conhecido pelos seus estudos dos fenômenos culturais e políticos contemporâneos, em "As Origens da Pós-Modernidade" (1999), conta que foi um amigo de Unamuno e Ortega, Frederico de Onís, que imprimiu o termo pela primeira vez, embora descrevendo um refluxo conservador dentro do próprio modernismo. Mas coube ao filósofo francês Jean-François Lyotard, com a publicação "A Condição Pós-Moderna" (1979), a expansão do uso do conceito. Em sua origem, pós-modernismo significava a perda da historicidade e o fim da "grande narrativa" -o que no campo estético significou o fim de uma tradição de mudança e ruptura, o apagamento da fronteira entre alta cultura e da cultura de massa e a prática da apropriação e da citação de obras do passado. A densa obra de Frederic Jameson "Pós-Modernismo" (1991), enumera como ícones desse movimento: na arte, Andy Warhol e a pop art, o fotorrealismo e o neo-expressionismo; na música, John Cage, mas também a síntese dos estilos clássico e "popular" que se vê em compositores como Philip Glass e Terry Riley e, também, o punk rock e a new wave"; no cinema, Godard; na literatura, William Burroughs, Thomas Pynchon e Ishmael Reed, de um lado, "e o nouveau roman francês e sua sucessão", do outro. Na arquitetura, entretanto, seus problemas teóricos são mais consistentemente articulados e as modificações da produção estética são mais visíveis.
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ABSTRACT: Senescence may be considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena during the process of aging. We investigated whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We conducted experiments to isolate zebrafish mutants expressing an apparent senescence phenotype during embryogenesis (embryonic senescence). Some of the genes we thereby identified had already been associated with cellular senescence and chronological aging in other organisms, but many had not yet been linked to these processes. Complete loss-of-function of developmentally essential genes induce embryonic (or larval) lethality, whereas it seems like their partial loss-of-function (i.e., decrease-of-function by heterozygote or hypomorphic mutations) still remains sufficient to go through the early developmental process because of its adaptive plasticity or rather heterozygote advantage. However, in some cases, such partial loss-of-function of genes compromise normal homeostasis due to haploinsufficiency later in adult life having many environmental stress challenges. By contrast, any heterozygote-advantageous genes might gain a certain benefit(s) (much more fitness) by such partial loss-of-function later in life. Physiological senescence may evolutionarily arise from both genetic and epigenetic drifts as well as from losing adaptive developmental plasticity in face of stress signals from the external environment that interacts with functions of multiple genes rather than effects of only a single gene mutation or defect. Previously uncharacterized developmental genes may thus mediate the aging process and play a pivotal role in senescence. Moreover, unexpected senescence-related genes might also be involved in the early developmental process and regulation. We wish to ascertain whether we can identify such genes promptly in a comprehensive manner. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates.Birth Defects Research Part C Embryo Today Reviews 09/2011; 93(3):229-48. DOI:10.1002/bdrc.20217 · 3.87 Impact Factor