Distinct expression patterns of the subunits of the CCR4-NOT deadenylase complex during neural development

Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2011; 411(2):360-4. DOI: 10.1016/j.bbrc.2011.06.148
Source: PubMed


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.

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    • "CNOT9 is frequently up-regulated in human breast cancer specimens and cell lines (Ajiro et al., 2009), and its expression is extremely low in normal human tissues, except testis, which suggests that CNOT9 is a cancer antigen (Ajiro et al., 2009). It should be noted, however, that the expression of CNOT9 is readily detectable in various murine adult tissues, including testis, ovary, thymus, brain, and lung (Chen et al., 2011). Short hairpin RNA (shRNA)-mediated suppression of CNOT9 drastically suppresses the proliferation of breast cancer cells (Ajiro et al., 2009). "
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    ABSTRACT: The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex serves as one of the major deadenylases of eukaryotes. Although it was originally identified and characterized in yeast, recent studies have revealed that the CCR4-NOT complex also exerts important functions in mammals, -including humans. However, there are some differences in the composition and functions of the CCR4-NOT complex between mammals and yeast. It is noteworthy that each subunit of the CCR4-NOT complex has unique, multifunctional roles and is responsible for various physiological phenomena. This heterogeneity and versatility of the CCR4-NOT complex makes an overall understanding of this complex difficult. Here, we describe the functions of each subunit of the mammalian CCR4-NOT complex and discuss the molecular mechanisms by which it regulates homeostasis in mammals. Furthermore, a possible link between the disruption of the CCR4-NOT complex and various diseases will be discussed. Finally, we propose that the analysis of mice with each CCR4-NOT subunit knocked out is an effective strategy for clarifying its complicated functions and networks in mammals.
    Full-text · Article · Aug 2014 · Frontiers in Genetics
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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. "
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    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.
    Full-text · Article · Sep 2011 · Protein & Cell
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