Transcriptional blackjack with <i>p21</i>: Figure 1.

Wood, Adam; Shilatifard, Ali

doi:10.1101/gad.1414506

Cited by 10 publications

(5 citation statements)

References 32 publications

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“…Chk1, which is primarily activated by ATR, 16,27 also seemed to be phosphorylated in etoposide-treated retinas. Further, the levels of p21, a protein that regulates cell cycle progression after DNA damage in a p53-dependent manner, 16,28 were found increased after etoposide treatment (Figure 3a). At the cellular level, etoposide induced the appearance of a large number of gH2AX nuclear foci after 30 min.…”

Section: Resultsmentioning

confidence: 99%

“…KU55933 reduced etoposidemediated increase of p21, a downstream substrate of ATM, but not of pChk1, primarily activated by the related ATR kinase. Conversely, DNA-PK inhibition did not affect either of these substrates 16,27,28 ( Figure 4c). Having confirmed the selective inhibitory effects of NU7026 and KU55933, we studied the cellular consequences of interfering with the intrinsic activity of DNA-PK.…”

Section: Resultsmentioning

confidence: 99%

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DNA-PK promotes the survival of young neurons in the embryonic mouse retina

2010

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Programmed cell death is a crucial process in neural development that affects mature neurons and glial cells, as well as proliferating precursors and recently born neurons at earlier stages. However, the regulation of the early phase of neural cell death and its function remain relatively poorly understood. In mouse models defective in homologous recombination or nonhomologous end-joining (NHEJ), which are both DNA double-strand break (DSB) repair pathways, there is massive cell death during neural development, even leading to embryonic lethality. These observations suggest that natural DSBs occur frequently in the developing nervous system. In this study, we have found that several components of DSB repair pathways are activated in the developing mouse retina at stages that coincide with the onset of neurogenesis. In short-term organotypic retinal cultures, we confirmed that the repair pathways can be modulated pharmacologically. Indeed, inhibiting the DNA-dependent protein kinase (DNA-PK) catalytic subunit, which is involved in NHEJ, with NU7026 increased caspase-dependent cell death and selectively reduced the neuron population. This observation concurs with an increase in the number of apoptotic neurons found after NU7026 treatment, as also observed in the embryonic scid mouse retina, a mutant that lacks DNA-PK catalytic subunit activity. Therefore, our results implicate the generation of DSB and DNA-PK-mediated repair in neurogenesis in the developing retina.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

DNA-PK promotes the survival of young neurons in the embryonic mouse retina

2010

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“…The distribution patterns of P-TEFb, NELF, and DSIF on the junB and MKP-1 genes are similar to those on the c-fos gene, suggesting that the transcription elongation machinery including those three factors is common to c-fos, junB, MKP-1, and possibly other rapidly inducible IEGs. However, when the induction of stress-activated p53-dependent genes was analyzed, some exceptions were found, notably the p21 gene, which can be transcribed in spite of DRB inhibition of CDK9 (20,55). Furthermore, our ChIP assays suggest that a housekeeping gene, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene, also appears to be occupied by P-TEFb, NELF, and DSIF (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Up-Regulation of P-TEFb by the MEK1-Extracellular Signal-Regulated Kinase Signaling Pathway Contributes to Stimulated Transcription Elongation of Immediate Early Genes in Neuroendocrine Cells

Fujita

Ryser

Piuz

et al. 2008

Molecular and Cellular Biology

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The positive elongation factor P-TEFb appears to function as a crucial C-terminal-domain (CTD) kinase for RNA polymerase II (Pol II) transcribing immediate early genes (IEGs) in neuroendocrine GH4C1 cells. Chromatin immunoprecipitation indicated that in resting cells Pol II occupied the promoter-proximal regions of the c-fos and junB genes, together with the negative elongation factors DSIF and NELF. Thyrotropinreleasing hormone (TRH)-induced recruitment of positive transcription elongation factor b (P-TEFb) abolished the pausing of Pol II and enhanced phosphorylation of CTD serine 2, resulting in transcription elongation. In addition, P-TEFb was essential for splicing and 3-end processing of IEG transcripts. Importantly, the MEK1-extracellular signal-regulated kinase (ERK) signaling pathway activated by TRH upregulated nuclear CDK9 and CDK9/cyclinT1 dimers (i.e., P-TEFb), facilitating the recruitment of P-TEFb to c-fos and other IEGs. Thus, in addition to established gene transcription control via promoter response elements, the MEK1-ERK signaling pathway controls transcription elongation by Pol II via the up-regulation of nuclear CDK9 integrated into P-TEFb.Gene transcription by RNA polymerase II (Pol II) proceeds through multiple steps: preinitiation, initiation, elongation, and termination (45). Historically, preinitiation and initiation have been considered the rate-limiting steps. Consequently, most studies on transcription control mechanisms have focused on the cis-and trans-acting elements in promoters. However, it has become increasingly evident in recent years that transcription elongation of many inducible genes is controlled by external stimuli (36, 51). These include the immediate early genes (IEGs) c-fos, c-myc, and MKP-1 (mitogen-activated protein kinase [MAPK] phosphatase 1), for which, based upon in vitro nuclear run-on experiments, a block to elongation has been postulated. Pol II transcription initiation of such genes is constitutive even under cellular resting conditions; however, transcripts are not elongated unless extracellular stimuli trigger intracellular signals, which permit transcription elongation to produce full-length transcripts (11,13,30,41,42,54).Progress through the transcription steps is tightly linked to the phosphorylation state of the C-terminal domain (CTD) in a large subunit of Pol II (37). The CTD consists of repeats of the YSPTSPS motif-52 repeats in mammalian cells. Various CTD kinases, including cyclin-dependent kinases (CDKs), selectively phosphorylate the serine residues at positions 2 and 5 (Ser-2 and Ser-5, respectively). The phosphorylation pattern of the CTD is changed in a dynamic fashion during the activation and attenuation of transcription. Pol II, which has initiated transcription, is phosphorylated on Ser-5, elongating Pol II in addition on 10,29,37,43). We have recently shown that the rate of c-fos transcription in vivo is continuously regulated at the level of elongation and that this regulation is reflected by the dynamic changes of Pol II CTD phosphory...

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“…In light of these observations, we and others have proposed that p21 WAF1 simultaneously targets growth-promoting genes and cdk activity to induce cell cycle arrest (9,10,19). However, although transcriptional functions of p21 WAF1 have been described following overexpression or in response to chemotherapy treatment, it remains to be determined whether this also occurs during OIS and which promoters are targeted by p21 WAF1 to restrain an abnormal oncogenic activity.…”

Section: Oncogene-induced Senescence (Ois)mentioning

confidence: 97%

Escape from p21-mediated Oncogene-induced Senescence Leads to Cell Dedifferentiation and Dependence on Anti-apoptotic Bcl-xL and MCL1 Proteins

Trécesson

Guillemin

Bélanger

et al. 2011

Journal of Biological Chemistry

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Oncogene-induced senescence (OIS) is a tumor suppressor response that induces permanent cell cycle arrest in response to oncogenic signaling. Through the combined activation of the p53-p21 and p16-Rb suppressor pathways, OIS leads to the transcriptional repression of proliferative genes. Although this protective mechanism has been essentially described in primary cells, we surprisingly observed in this study that the OIS program is conserved in established colorectal cell lines. In response to the RAS oncogene and despite the inactivation of p53 and p16 INK4 , HT29 cells enter senescence, up-regulate p21 WAF1 , and induce senescence-associated heterochromatin foci formation. The same effect was observed in response to B-RAF v600E in LS174T cells. We also observed that p21 WAF1 prevents the expression of the CDC25A and PLK1 genes to induce cell cycle arrest. Using ChIP and luciferase experiments, we have observed that p21 WAF1 binds to the PLK1 promoter to induce its down-regulation during OIS induction. Following 4 -5 weeks, several clones were able to resume proliferation and escape this tumor suppressor pathway. Tumor progression was associated with p21 WAF1 down-regulation and CDC25A and PLK1 reexpression. In addition, OIS and p21 WAF1 escape was associated with an increase in DNA damage, an induction of the epithelialmesenchymal transition program, and an increase in the proportion of cells expressing the CD24 low /CD44 high phenotype. Results also indicate that malignant cells having escaped OIS rely on survival pathways induced by Bcl-xL/MCL1 signaling. In light of these observations, it appears that the transcriptional functions of p21 WAF1 are active during OIS and that the inactivation of this protein is associated with cell dedifferentiation and enhanced survival.

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Transcriptional blackjack with p21: Figure 1.

Cited by 10 publications

References 32 publications

DNA-PK promotes the survival of young neurons in the embryonic mouse retina

DNA-PK promotes the survival of young neurons in the embryonic mouse retina

Up-Regulation of P-TEFb by the MEK1-Extracellular Signal-Regulated Kinase Signaling Pathway Contributes to Stimulated Transcription Elongation of Immediate Early Genes in Neuroendocrine Cells

Escape from p21-mediated Oncogene-induced Senescence Leads to Cell Dedifferentiation and Dependence on Anti-apoptotic Bcl-xL and MCL1 Proteins

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