Epigenetic Control of rDNA Loci in Response to Intracellular Energy Status

Murayama, Akiko; Ohmori, Kazuji; Fujimura, Akiko; Minami, Hiroshi; Yasuzawa-Tanaka, Kayoko; Kuroda, Takeshi; Oie, Shohei; Daitoku, Hiroaki; Okuwaki, Mitsuru; Nagata, Kyosuke; Fukamizu, Akiyoshi; Kimura, Kazuhiro; Shimizu, Toshiyuki; Yanagisawa, Junn

doi:10.1016/j.cell.2008.03.030

Cited by 370 publications

(376 citation statements)

References 41 publications

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“…This protein promotes chromatin compaction and repression of gene expression. Repression of ribosomal RNA transcription by SIRT1 helps shut down ribosomal synthesis and protein translation (Murayama et al, 2008). On the other hand, acetylation, which is a post-transcriptional modification of many proteins, is influenced by glucose levels, as acetyl groups are derived from glucose metabolism.…”

Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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“…The mean DCT value of the control sample was used in each experiment to calculate the DDCT value of sample replicates. POLR1A, p21 and the internal control b-glucuronidase mRNAs were quantified with TaQMan Gene Expression Assays primers and probe kits (Applied Biosystems); primers and UPL probe (Roche Diagnostics, Milan, Italy) for rpL11 and rpL5 were chosen with the Roche online primer design tool, primers for SYBR Green real-time PCR analysis of human Bax, PUMA and rat p21, Bax, and PUMA were designed using the same online tool; primers for human and rat 45S rRNA have been already described by Grandori et al (2005)and Murayama et al (2008), respectively. All sequences are available upon request.…”

Section: Animalsmentioning

confidence: 99%

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

et al. 2011

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Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up-and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.

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“…Chromatin immunoprecipitation assay was performed according to the published procedure (Murayama et al, 2008). The primers for real-time PCR are forward: TATGAA TCACTTCTGGAGTG A; reverse: GAGCGTTAGATAACA TTTGCC for pS2 gene upstream region.…”

Section: Chip and Real-time Pcr Detectionmentioning

confidence: 99%

“…Real-time reverse transcription-PCR Real-time reverse transcription-PCR was performed essentially as described earlier (Murayama et al, 2008). Tissues and cells were homogenized in 1 ml of Isogen and total RNA was extracted according to the instruction manual (Nippon gene, Tokyo, Japan).…”

Section: Chip and Real-time Pcr Detectionmentioning

confidence: 99%

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

et al. 2009

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Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-a (ERa) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ERa, and found that KLF4 bound to the DNA-binding region of ERa. KLF4 thus inhibits the binding of ERa to estrogen response elements in promoter regions, resulting in a reduction in ERa target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ERa by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ERa. As both p53 and ERa are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers.

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Epigenetic Control of rDNA Loci in Response to Intracellular Energy Status

Cited by 370 publications

References 41 publications

Sugar-free approaches to cancer cell killing

Sugar-free approaches to cancer cell killing

The balance between rRNA and ribosomal protein synthesis up- and downregulates the tumour suppressor p53 in mammalian cells

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

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