The PTEN Phosphatase Controls Intestinal Epithelial Cell Polarity and Barrier Function: Role in Colorectal Cancer Progression

Langlois, Marie‐Josée; Bergeron, Sébastien; Bernatchez, Gérald; Boudreau, François; Saucier, Caroline; Perreault, Nathalie; Carrier, Julie; Rivard, Nathalie

doi:10.1371/journal.pone.0015742

Cited by 61 publications

(46 citation statements)

References 71 publications

(105 reference statements)

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“…6C). The identified positive correlation between transcription of repeats, induction of an IFN response, and sensitivity to 5-aza-dC supports our model in which tumors with reduced p53 function (36)(37)(38) are prone to activation of transcription of repeats under conditions of reduced DNA methylation. These results suggest that the sensitivity of tumor cells with silent repeats to 5-aza-dC (i.e., the drug decitabine approved for treatment of myelodysplastic syndrome and considered for anticancer use) may depend on whether they have functional p53.…”

Section: Structural Properties Of Major Classes Of P53-controlled Repsupporting

confidence: 82%

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

Leonova

Brodsky

Lipchick

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

232

254

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Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was observed in p53-deficient but not in p53 wild-type mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine. The abundance of these transcripts exceeded the level of β-actin mRNA by more than 150-fold. Accumulation of these transcripts, which are capable of forming double-stranded RNA (dsRNA), was accompanied by a strong, endogenous, apoptosis-inducing type I IFN response. This phenomenon, which we named "TRAIN" (for "transcription of repeats activates interferon"), was observed in spontaneous tumors in two models of cancer-prone mice, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation in cancer. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats and provide a plausible explanation for the deregulation of IFN function frequently seen in tumors. Overall, this work reveals roles for p53 and IFN that are key for genetic stability and therefore relevant to both tumorigenesis and the evolution of species.interferon alpha-beta receptor | RNA sequencing | epigenetic repression | microarray hybridization

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Section: Structural Properties Of Major Classes Of P53-controlled Repsupporting

confidence: 82%

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

Leonova

Brodsky

Lipchick

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

232

254

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“…In subsequent studies, also using human colon cancer cells, it was found that the PtdIns(3,4,5)P 3 3-phosphatase PTEN localizes to the apical membrane explaining the lack of PtdIns(3,4,5)P 3 in that compartment. Indeed, PTEN downregulation disrupted intestinal epithelial polarity and increased the invasiveness of human colon cancer cells (851). A possible link between PtdIns(4,5)P 2 and the apical polarity was established when annexin2, which had been previously shown to bind PtdIns(4,5)P 2 (1268), was found to be enriched in the apical membranes and also to recruit Cdc42, a small GTP binding protein.…”

Section: Epithelial Cell Polaritymentioning

confidence: 99%

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Balla

2013

Physiological Reviews

1,359

1,655

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Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

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“…We next examined the effects of silencing PTEN on centrosome levels of PLK-1 and γ-tubulin during mitosis by immunofluorescence, since both PLK-1 and (phosphatidylinositol-3,4,5-trisphosphate). 13,14 Nuclear PTEN is important for inducing cell cycle arrest and maintaining chromosome stability; these processes are, at least in part, independent of Akt inhibition. 15,16 Interestingly, PTEN −/− mouse embryonic fibroblasts (MEFs) escape taxol-mediated mitotic arrest more quickly than wild type cells, suggesting that PTEN is important for a mitotic spindle checkpoint.…”

Section: Introductionmentioning

confidence: 99%

The PTEN-Akt pathway impacts the integrity and composition of mitotic centrosomes

Leonard

Hill²,

Bubulya³

et al. 2013

Cell Cycle

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Loss of the tumor suppressor PTEN is observed in many human cancers that display increased chromosome instability and aneuploidy. The subcellular fractions of PTEN are associated with different functions that regulate cell growth, invasion and chromosome stability. In this study, we show a novel role for PTEN in regulating mitotic centrosomes. PTEN localization at mitotic centrosomes peaks between prophase and metaphase, paralleling the centrosomal localization of PLK-1 and γ-tubulin and coinciding with the time frame of centrosome maturation. In primary keratinocytes, knockdown of PTEN increased whole-cell levels of γ-tubulin and PLK-1 in an Akt-dependent manner and had little effect on recruitment of either protein to mitotic centrosomes. Conversely, knockdown of PTEN reduced centrosomal levels of pericentrin in an Akt-independent manner. Inhibition of Akt activation with MK2206 reduced the whole-cell and centrosome levels of PLK-1 and γ-tubulin and also prevented the recruitment of PTEN to mitotic centrosomes. This reduction in centrosome-associated proteins upon inhibition of Akt activity may contribute to the increase in defects in centrosome number and separation observed in metaphase cells. Concomitant PTEN knockdown and Akt inhibition reduced the frequency of metaphase cells with centrosome defects when compared with MK2206 treatment alone, indicating that both PTEN and pAkt are required to properly regulate centrosome composition during mitosis. The findings presented in this study demonstrate a novel role for PTEN and Akt in controlling centrosome composition and integrity during mitosis and provide insight into how PTEN functions as a multifaceted tumor suppressor.

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The PTEN Phosphatase Controls Intestinal Epithelial Cell Polarity and Barrier Function: Role in Colorectal Cancer Progression

Cited by 61 publications

References 71 publications

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

The PTEN-Akt pathway impacts the integrity and composition of mitotic centrosomes

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