An Oct4-pRb Axis, Controlled by MiR-335, Integrates Stem Cell Self-Renewal and Cell Cycle Control

Schoeftner, Stefan; Scarola, Michele; Comisso, Elisa; Schneider, Claudio; Benetti, Roberta

doi:10.1002/stem.1315

Cited by 41 publications

(43 citation statements)

References 34 publications

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“…Such a defect in self-renewal can be rescued by ectopic expression of a Tex10 transgene that lacks the shRNA target site, excluding off-target effects of the shRNAs (Figures S2B–C). Of note, a similar requirement of the core pluripotency factors OSN for efficient G1/S transition in both human (Card et al, 2008; Zhang et al, 2009) and mouse (Schoeftner et al, 2013) ESCs has also been reported, suggesting a potential functional interaction between Tex10 and OSN.…”

Section: Resultsmentioning

confidence: 57%

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming

et al. 2015

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SUMMARY Super-enhancers (SEs) are large clusters of transcriptional enhancers that are co-occupied by multiple lineage specific transcription factors driving expression of genes that define cell identity. In embryonic stem cells (ESCs), SEs are highly enriched for the core pluripotency factors Oct4, Sox2, and Nanog. In this study, we sought to dissect the molecular control mechanism of SE activity in pluripotency and reprogramming. Starting from a protein interaction network surrounding Sox2, we identified Tex10 as a key pluripotency factor that plays a functionally significant role in ESC self-renewal, early embryo development, and reprogramming. Tex10 is enriched at SEs in a Sox2-dependent manner and coordinates histone acetylation and DNA demethylation at SEs. Tex10 activity is also important for pluripotency and reprogramming in human cells. Our study therefore highlights Tex10 as a core component of the pluripotency network and sheds light on its role in epigenetic control of SE activity for cell fate determination.

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Section: Resultsmentioning

confidence: 57%

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming

et al. 2015

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“…Conversely, other studies had found that a delay in G1-S phase transition in human ESCs (hESCs) could up-regulate dephosphorylated pRb and induce the loss of Oct-4 (Filipczyk et al, 2007). In addition, some studies confirmed that high Oct4 expression increased the inhibitors of the major pRb phosphatase to maintain the hyperphosphorylation of pRb, which influenced the maintenance of stemness and the cell cycle control of stem cells (Schoeftner et al, 2013). Here, we determined that prolonged anesthesia with dexmedetomidine or fentanyl caused rising cell numbers in the G1 phase and down-regulation of Oct4 and Sox2 gene expression.…”

Section: Discussionmentioning

confidence: 99%

Effects of prolonged anesthesia with dexmedetomidine, fentanyl, or remifentanil on the self-renewal of mouse embryonic stem cells

Cai

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Previous study has indicated that exposure to anesthesia in early development leads to neuro-apoptosis and is followed by longterm cognitive dysfunction. Given that larger numbers of pregnant women currently receive anesthesia during the first trimester, we wanted to mimic this process in vitro using mouse embryonic stem cells (mESCs) and to explore how different anesthetics affect the self-renewal of mESCs. In the present study, mESCs were exposed to dexmedetomidine, fentanyl, or remifentanil at clinical concentrations for 48 h. The mESCs were then analyzed for cell proliferation and apoptosis. Furthermore, we used flow cytometry to analyze the cell cycle and quantitative real-time polymerase chain reaction to detect the gene expression during the cell cycle as well as the relevant stemness markers. We found that prolonged anesthesia with dexmedetomidine or fentanyl significantly inhibited mESC proliferation, with fewer cell numbers as well as decreased expression of cyclin B and cyclin E mRNA compared to that in the control group; meanwhile, p21 and RB2 gene expression was increased. Additionally, increases or decreases in the proportion of cells in the G1 and S phases, respectively, were observed in the dexmedetomidine-and fentanyl-treated groups. These anesthetics also repressed the gene expression of mESC stemness makers such as Oct4 and Sox2. However, remifentanil seemed to have no significant influence on the self-renewal of mESCs. These results demonstrated that prolonged anesthesia with dexmedetomidine or fentanyl, but not remifentanil, inhibited mESC proliferation by blocking the G1 to S transition, and repressed the maintenance of mESC stemness.

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“…The loss of checkpoint control is required for cancer initiation and development (43,44). Thus, there is a clear direct connection between miRNAs and cancer formation, which will not be discussed further in the present review.…”

Section: Signalling Cascades With Microrna Interactionmentioning

confidence: 95%

“…Lynch et al (42) reported that miR-335 was able to suppress metastasis of neuroblastoma cells by directly repressing the downstream effector proteins of the transforming growth factor (TGF)-β pathway, namely Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) and mitogen-activated protein kinase 1 (MAPK1), which consequently reduced the phosphorylation levels of myosin light chain and inhibited the invasiveness of neuroblastoma cells. In addition to its regulatory function in signaling pathways, miR-335 has roles in at least two pathways involved in cell cycle control, namely ataxia telangiectasia mutated (ATM)-dependent DNA damage control (43) and octamer-binding transcription factor 4-retinoblastoma protein (Oct4-pRB)-dependent stem cell renewal/cell cycle control (44). In the ATM pathway, irradiation-activated ATM downregulates miR-335 via cyclic adenosine monophosphate response element binding protein, which subsequently activates C terminal binding protein interaction protein, which in turn recruits breast cancer 1, early onset to double strand breaks (43).…”

Section: Mir-21 In Cd133mentioning

confidence: 99%

“…During stem cell renewal, miR-335 is able to regulate the cell cycle by controlling the activities of the Oct4-pRb signaling pathway. When differentiation begins, miR-335 is upregulated, and thus downregulates the expression of Oct4, which impairs the rapid division cycle of stem cell renewal (44). Previous studies have demonstrated that the expression levels of miR-335 are cancer type-specific.…”

Section: Mir-21 In Cd133mentioning

confidence: 99%

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Diverse microRNAs with convergent functions regulate tumorigenesis

2015

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Abstract. MicroRNAs (miRNAs) regulate several biological processes, including tumorigenesis. In order to comprehend the roles of miRNAs in cancer, various screens were performed to investigate the changes in the expression levels of miRNAs that occur in different types of cancer. The present review focuses on the results of five recent screens, whereby a number of overlapping miRNAs were identified to be downregulated or differentially regulated, whereas no miRNAs were observed to be frequently upregulated. Furthermore, the majority of the miRNAs that were common to >1 screen were involved in signaling networks, including wingless-related integration site, receptor tyrosine kinase and transforming growth factor-β, or in cell cycle checkpoint control. The present review will discuss the aforementioned miRNAs implicated in cell cycle checkpoint control and signaling networks. IntroductionMicroRNAs (miRNAs) are small non-coding RNAs of 21-25 nucleotides in length that control gene expression via post-transcriptional regulation (1). Contrasting with the maturation process of normal coding RNAs, the miRNA genes are initially transcribed by RNA polymerase II into a primary transcript in the nucleus, where the hairpin structure is processed into precursor miRNA by a microprocessing complex that includes Drosha and DiGeorge syndrome chromosomal (or critical) region 8 (DGCR8) (1). Subsequently, the ~70 nucleotide-long precursor miRNA is exported into the cytoplasm, where it undergoes secondary processing by Dicer, and one strand of the hairpin is then incorporated into a ribonucleoprotein complex known as miRNA-induced silencing complex (1). Once matured, a single miRNA may target miscellaneous messenger RNAs (mRNAs), and an individual mRNA may be regulated by various miRNAs (1). miRNAs have significant roles during stem cell maintenance and differentiation (2). In addition, they have frequently been used as markers for certain types of cancer cells, by comparing the measured levels of known miRNAs with those present in their wild-type counterparts (2,3). Screens investigating differential expression of miRNAs in various cancer cell populations have been previously performed. The present review will focus on the results of five screens conducted in the past recent years, which investigated prostate cancer (3), neuroblastoma (4), pancreatic cancer (5), chronic myeloid leukemia (CML) (6) and osteosarcoma cells (7). Specifically, Liu et al (3) used three prostate cancer metastatic cell lines, namely LAPC9, LAPC4 and Du145 [bone cluster of differentiation (CD)44 + /CD44 -subpopulation sorting based on LAPC9, LAPC4 and Du145 cell lines; side population (SP)/non-SP sorting based on LAPC9 cell line; and CD133 + /CD133 -subpopulation sorting based on LAPC4 cell line], and compared the expression levels of miscellaneous miRNAs (with vs. without markers) in these cells. Following testing for 324 DGCR8 miRNAs by reverse transcription-quantitative polymerase chain reaction, 137 miRNAs were identified to be expressed in the three ce...

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An Oct4-pRb Axis, Controlled by MiR-335, Integrates Stem Cell Self-Renewal and Cell Cycle Control

Cited by 41 publications

References 34 publications

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity in Pluripotency and Reprogramming

Effects of prolonged anesthesia with dexmedetomidine, fentanyl, or remifentanil on the self-renewal of mouse embryonic stem cells

Diverse microRNAs with convergent functions regulate tumorigenesis

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