Novel Nucleolar Pathway Connecting Intracellular Energy Status with p53 Activation

Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8577, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2011; 286(23):20861-9. DOI: 10.1074/jbc.M110.209916
Source: PubMed


In response to a shortage of intracellular energy, mammalian cells reduce energy consumption and induce cell cycle arrest,
both of which contribute to cell survival. Here we report that a novel nucleolar pathway involving the energy-dependent nucleolar
silencing complex (eNoSC) and Myb-binding protein 1a (MYBBP1A) is implicated in these processes. Namely, in response to glucose
starvation, eNoSC suppresses rRNA transcription, which results in a reduction in nucleolar RNA content. As a consequence,
MYBBP1A, which is anchored to the nucleolus via RNA, translocates from the nucleolus to the nucleoplasm. The translocated
MYBBP1A induces acetylation and accumulation of p53 by enhancing the interaction between p300 and p53, which eventually leads
to the cell cycle arrest (or apoptosis). Taken together, our results indicate that the nucleolus works as a sensor that transduces
the intracellular energy status into the cell cycle machinery.

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    • "We previously reported that MYBBP1A interacts with p53 and activates its transcriptional capacity. MYBBP1A localizes predominantly in the nucleolus; however, it translocates from the nucleolus to the nucleoplasm in response to cellular stress and activates p53 [13,14,35]. Similar to other kinds of stress, detached conditions induce p53 acetylation and target gene transcription in an MYBBP1A-dependent manner (Figures 6 and 7A). "
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    ABSTRACT: Background Tumor suppressor p53 is mutated in a wide variety of human cancers and plays a critical role in anoikis, which is essential for preventing tumorigenesis. Recently, we found that a nucleolar protein, Myb-binding protein 1a (MYBBP1A), was involved in p53 activation. However, the function of MYBBP1A in cancer prevention has not been elucidated. Methods Relationships between MYBBP1A expression levels and breast cancer progression were examined using patient microarray databases and tissue microarrays. Colony formation, xenograft, and anoikis assays were conducted using cells in which MYBBP1A was either knocked down or overexpressed. p53 activation and interactions between p53 and MYBBP1A were assessed by immunoprecipitation and western blot. Results MYBBP1A expression was negatively correlated with breast cancer tumorigenesis. In vivo and in vitro experiments using the breast cancer cell lines MCF-7 and ZR-75-1, which expresses wild type p53, showed that tumorigenesis, colony formation, and anoikis resistance were significantly enhanced by MYBBP1A knockdown. We also found that MYBBP1A binds to p53 and enhances p53 target gene transcription under anoikis conditions. Conclusions These results suggest that MYBBP1A is required for p53 activation during anoikis; therefore, it is involved in suppressing colony formation and the tumorigenesis of breast cancer cells. Collectively, our results suggest that MYBBP1A plays a role in tumor prevention in the context of p53 activation.
    Full-text · Article · Feb 2013 · BMC Cancer
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    • "The observed functional attributes of Mybbp1a are in accordance with those previously reported for other rDNA-associated epigenetic repressors, such as JHDM1B [33] and energy-dependent nucleolar silencing complex (eNoSC) [34]. Interestingly, an energy-sensing nucleolar pathway involving eNoSC and Mybbp1a was recently implicated in the nucleolar stress-associated regulation of p53 [35]. Possible functional and physical interaction between Mybbp1a and these factors may thus contribute to a robust and dynamic expression of the ribosomal RNA. "
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    ABSTRACT: Transcription of the ribosomal RNA gene repeats by Pol I occurs in the nucleolus and is a fundamental step in ribosome biogenesis and protein translation. Due to tight coordination between ribosome biogenesis and cell proliferation, transcription of rRNA and stable maintenance of rDNA clusters are thought to be under intricate control by intercalated mechanisms, particularly at the epigenetic level. Here we identify the nucleolar protein Myb-binding protein 1a (Mybbp1a) as a novel negative regulator of rRNA expression. Suppression of rDNA transcription by Mybbp1a was linked to promoter regulation as illustrated by its binding to the chromatin around the hypermethylated, inactive rDNA gene promoters. Our data further showed that downregulation of Mybbp1a abrogated the local DNA methylation levels and histone marks associated with gene silencing, and altered the promoter occupancy of various factors such UBF and HDACs, consequently leading to elevated rRNA expression. Mechanistically, we propose that Mybbp1a maintains rDNA repeats in a silenced state while in association with the negative epigenetic modifiers HDAC1/2. Results from our present work reveal a previously unrecognized co-repressor role of Mybbp1a in rRNA expression. They are further consistent with the scenario that Mybbp1a is an integral constituent of the rDNA epigenetic regulation that underlies the balanced state of rDNA clusters.
    Full-text · Article · Jun 2012 · Journal of Biomedical Science
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    ABSTRACT: At its broadest sense, to say that a phenotype is epigenetic suggests that it occurs without changes in DNA sequence, yet is heritable through cell division and occasionally from one organismal generation to the next. Since gene regulatory changes are oftentimes in response to environmental stimuli and may be retained in descendent cells, there is a growing expectation that one's experiences may have consequence for subsequent generations and thus impact evolution by decoupling a selectable phenotype from its underlying heritable genotype. But the risk of this overbroad use of "epigenetic" is a conflation of genuine cases of heritable non-sequence genetic information with trivial modes of gene regulation. A look at the term "epigenetic" and some problems with its increasing prevalence argues for a more reserved and precise set of defining characteristics. Additionally, questions arising about how we define the "sequence independence" aspect of epigenetic inheritance suggest a form of genome evolution resulting from induced polymorphisms at repeated loci (e.g., the rDNA or heterochromatin).
    Full-text · Article · Jan 2012
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