Identification of pathways regulating cell size and cell-cycle progression by RNAi

Björklund, Mikael; Taipale, Minna; Varjosalo, Markku; Saharinen, Juha; Lahdenperä, Juhani; Taipale, Jussi

doi:10.1038/nature04469

Cited by 247 publications

(264 citation statements)

References 29 publications

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“…The intimate relationship between protein biosynthesis and cell cycle progression through G1 that we observed is consistent with previous observations linking protein synthesis with G1 transit (Unger and Hartwell, 1976;Bedard et al, 1981;Moreno and Nurse, 1994), with connections between ribosome biogenesis and cell size regulation at Start (Jorgensen et al, 2002(Jorgensen et al, , 2004, and with links between translation rate and G1 (Polymenis and Schmidt, 1997) and provides a global view of cellular processes that contribute to passage through the cell cycle commitment point in G1, Start. There is concordance between our G1 data and that derived from cell cycle screening of Drosophila cells after gene product depletion by RNAi (Bjorklund et al, 2006) in that both screens show clear involvement of protein biosynthesis pathways in G1 transit. However, in the Drosophila screen the genes identified were largely ribosomal subunit genes, whereas our data also illustrate the roles of ribosome assembly factors, and tRNA synthesis, processing, and charging proteins in regulating G1.…”

Section: Discussionsupporting

confidence: 64%

“…In this respect our screen is conceptually similar to a recent cell cycle screen in Drosophila cells using gene product depletion by RNA-mediated interference (RNAi; Bjorklund et al, 2006). One reasonable explanation for the observation that in some strains the cell cycle phenotype is a delay rather than an arrest and that in some strains Ͻ100% of cells accumulate at the relevant cell cycle stage is that promoter shut-off will not uniformly result in protein depletion within the timeframe of the experiment.…”

Section: Discussionmentioning

confidence: 71%

“…We anticipate that many of the connections between essential cellular processes and cell division cycle progression illustrated here will be conserved in humans. Indeed, a number of pathways that we find are important for cell cycle progression in yeast are also important for cell cycle progression in Drosophila (Bjorklund et al, 2006), encouraging the view that this global analysis of the connections between essential genes and the cell cycle will be useful in dissecting the network of processes that impinge on progression through the cell cycle in metazoans.…”

Section: Discussionmentioning

confidence: 85%

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A Survey of Essential Gene Function in the Yeast Cell Division Cycle

Peña‐Castillo

Mnaimneh

et al. 2006

MBoC

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Mutations impacting specific stages of cell growth and division have provided a foundation for dissecting mechanisms that underlie cell cycle progression. We have undertaken an objective examination of the yeast cell cycle through flow cytometric analysis of DNA content in TetO 7 promoter mutant strains representing 75% of all essential yeast genes. More than 65% of the strains displayed specific alterations in DNA content, suggesting that reduced function of an essential gene in most cases impairs progression through a specific stage of the cell cycle. Because of the large number of essential genes required for protein biosynthesis, G1 accumulation was the most common phenotype observed in our analysis. In contrast, relatively few mutants displayed S-phase delay, and most of these were defective in genes required for DNA replication or nucleotide metabolism. G2 accumulation appeared to arise from a variety of defects. In addition to providing a global view of the diversity of essential cellular processes that influence cell cycle progression, these data also provided predictions regarding the functions of individual genes: we identified four new genes involved in protein trafficking (NUS1, PHS1, PGA2, PGA3), and we found that CSE1 and SMC4 are important for DNA replication. INTRODUCTIONCell division is a fundamental biological process that in all organisms consists of a series of closely coordinated events. In the budding yeast Saccharomyces cerevisiae, the cell division cycle begins with an initial growth phase, G1, during which time the cell increases in mass and volume. The transition from G1 into S phase is marked by progression through Start (the point of commitment to cell division), initiation of nuclear DNA synthesis, and the emergence of a bud that will form the new daughter cell. S phase is followed by a second growth phase, G2, which is in turn followed by nuclear division, and then cell separation. A very similar series of events occurs in all eukaryotes, with the obvious exception of bud emergence. Because of the fundamental biological importance of cell cycle progression and its importance in both human development and diseases such as cancer, identification of the molecular determinants of specific stages of the eukaryotic cell cycle has been a subject of intense study for several decades.The morphological landmarks of the cell cycle stages in budding yeast, most notably the size of the bud relative to the size of the mother cell, allows the identification of mutants blocked at specific stages of the cell cycle and thereby forms the basis for the classic cell cycle screens (Hartwell et al., 1970;Culotti and Hartwell, 1971;Hartwell, 1971aHartwell, , 1971bHartwell, , 1973Moir et al., 1982). These genetic screens, using conditional temperature-sensitive mutants, identified more than 50 genes that are required for specific stages in the cell division cycle and so were termed CDC genes. On average 4.6 alleles were identified for each CDC gene in the original screens, suggesting the number of cdc mutan...

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 85%

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A Survey of Essential Gene Function in the Yeast Cell Division Cycle

Peña‐Castillo

Mnaimneh

et al. 2006

MBoC

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“…The cell cycle can be divided into two distinct phases: the synthesis (S) phase, in which DNA is replicated, and the mitosis (M) phase, in which cell division occurs. In animal cells, the components required for these phases are regulated by extracellular growth factors, and they are found mainly in the two gap phases, G 1 (between M and [25] . Platonin has been reported to induce significant G 0 /G 1 arrest of a panel of human leukemic cell lines, including U937, HL-60, K562, NB4, and THP-1 [16] .…”

Section: Discussionmentioning

confidence: 99%

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Chang

Uen²,

Chen

et al. 2011

Acta Pharmacol Sin

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Aim: To examine the inhibitory actions of the immunoregulator platonin against proliferation of rat vascular smooth muscle cells (VSMCs). Methods: VSMCs were prepared from the thoracic aortas of male Wistar rats. Cell proliferation was examined using MTT assays. Cell cycles were analyzed using flow cytometry. c-Jun N-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, AKT, and c-Jun phosphorylation or p27 expression were detected using immunoblotting. Results: Pretreatment with platonin (1-5 μmol/L) significantly suppressed VSMC proliferation stimulated by PDGF-BB (10 ng/mL) or 10% fetal bovine serum (FBS), and arrested cell cycle progression in the S and G 2 /M phases. The same concentrations of platonin significantly inhibited the phosphorylation of JNK1/2 but not ERK1/2 or AKT in VSMCs stimulated by PDGF-BB. Furthermore, platonin also attenuated c-Jun phosphorylation and markedly reversed the down-regulation of p27 expression after PDGF-BB stimulation. Conclusion: Platonin inhibited VSMC proliferation, possibly via inhibiting phosphorylation of JNK1/2 and c-Jun, and reversal of p27 down-regulation, thereby leading to cell cycle arrest at the S and G 2 /M phases. Thus, platonin may represent a novel approach for lowering the risk of abnormal VSMC proliferation and related vascular diseases.

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“…Cells were then mock treated or irradiated with 10 Gy using a 137 Cs γ-ray source (BioBeam 8000, STS) or with 30 J/m 2 UV-C (Stratalinker, Stratagene). Medium with 10% serum was added, and cells were cultured for 2 additional days before DNA content analysis with flow cytometry as described previously (19). In some experiments, caffeine was added to a 2 mmol/L final concentration 15 minutes before irradiation and kept until DNA content analysis to inhibit DNA damage checkpoint activation.…”

Section: Functional Analysesmentioning

confidence: 99%

Mutations in the Circadian Gene CLOCK in Colorectal Cancer

Alhopuro

Björklund

Sammalkorpi

et al. 2010

Molecular Cancer Research

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The circadian clock regulates daily variations in physiologic processes. CLOCK acts as a regulator in the circadian apparatus controlling the expression of other clock genes, including PER1. Clock genes have been implicated in cancer-related functions; in this work, we investigated CLOCK as a possible target of somatic mutations in microsatellite unstable colorectal cancers. Combining microarray gene expression data and public gene sequence information, we identified CLOCK as 1 of 790 putative novel microsatellite instability (MSI) target genes. A total of 101 MSI colorectal carcinomas (CRC) were sequenced for a coding microsatellite in CLOCK. The effect of restoring CLOCK expression was studied in LS180 cells lacking wild-type CLOCK by stably expressing GST-CLOCK or glutathione S-transferase empty vector and testing the effects of UV-induced apoptosis and radiation by DNA content analysis using flow cytometry. Putative novel CLOCK target genes were searched by using ChIP-seq. CLOCK mutations occurred in 53% of MSI CRCs. Restoring CLOCK expression in cells with biallelic CLOCK inactivation resulted in protection against UV-induced apoptosis and decreased G 2 -M arrest in response to ionizing radiation. Using ChIP-Seq, novel CLOCK-binding elements were identified near DNA damage genes p21, NBR1, BRCA1, and RAD50. CLOCK is shown to be mutated in cancer, and altered response to DNA damage provides one plausible mechanism of tumorigenesis. Mol Cancer Res; 8(7); 952-60. ©2010 AACR.

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Identification of pathways regulating cell size and cell-cycle progression by RNAi

Cited by 247 publications

References 29 publications

A Survey of Essential Gene Function in the Yeast Cell Division Cycle

A Survey of Essential Gene Function in the Yeast Cell Division Cycle

Platonin inhibited PDGF-BB-induced proliferation of rat vascular smooth muscle cells via JNK1/2-dependent signaling

Mutations in the Circadian Gene CLOCK in Colorectal Cancer

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