E2F2 converts reversibly differentiated PC12 cells to an irreversible, neurotrophin-dependent state

Persengiev, Stephan P.; Li, Junqing; Poulin, Matthew L.; Kilpatrick, Daniel L.

doi:10.1038/sj.onc.1204663

Cited by 21 publications

(17 citation statements)

References 49 publications

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“…NGF is known to regulate some members of the E2F family in PC12 cells (Persengiev et al, 1999(Persengiev et al, , 2001) and recent evidence indicates that E2Fs can transcriptionally regulate N-myc levels (Strieder and Lutz, 2003). We found that at 48 h NGF induced a 5.5-fold decrease in N-myc levels, a twofold decrease in E2F1 and a 2.8-fold decrease in E2F2 levels in 15N-TrkA (Figure 4b).…”

Section: Activation Of Trka Pathways Decreases Cell Numbermentioning

confidence: 52%

NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number

2003

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In neuroblastoma (NB), expression of the TrkA receptor is correlated with good prognosis while N-myc amplification is correlated with poor prognosis. Decreased N-myc levels are key to controlling growth and inducing differentiation in NB cells. In this report, we detail mechanisms by which nerve growth factor (NGF) decreases N-myc levels in TrkA-transfected NB cells and its effect on NB cell proliferation. NGF induced a decrease in N-myc mRNA within 1 h of treatment that occurred in the presence of cycloheximide. The stability of N-myc mRNA was not affected by NGF, indicating a transcriptional control of N-myc mRNA by NGF. NGF but not brain-derived neurotrophic factor (BDNF) decreased N-myc levels demonstrating that p75 alone was not involved. The NGF-induced decrease in N-myc expression was blocked by the Trk tyrosine kinase (TK) antagonist K252a indicating that signals transduced by Trk TK downstream targets were involved. Pharmacologic inhibitors implicated the mitogen-activated protein kinase (MAPK) path. This was supported by the finding that expression of a constitutively activated component of the MAPK path, MAPK kinase (MEK), decreased Nmyc levels. Alterations in the level of N-myc are known to alter NB cell cycle progression by affecting the levels of E2Fs and p27 kip1 . Consistent with these findings, NGF decreased NB cell number and decreased cyclin Edependent kinase activity via an increase in p27 kip1 . Thus, our results indicate that the MAP kinase is selectively involved in the NGF-induced N-myc downregulation through a transcriptional mechanism. Furthermore, NGF affects the time required for 15N TrkA cells to complete a replication cycle by decreasing N-myc, E2Fs, cyclin E kinase activity and increasing p27 kip1 binding to cyclin E kinase.

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Section: Activation Of Trka Pathways Decreases Cell Numbermentioning

confidence: 52%

NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number

2003

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“…Furthermore, E2F2 has been shown to have a tissue-restricted role in erythropoiesis and in neuronal differentiation. 22,23 Although structurally very similar to E2F2, E2F1 and E2F3 do not appear to inhibit DNA synthesis, 18,19,24,25 suggesting that this is a specific function of E2F2, not shared by the other members of the E2F subfamily. We have now investigated the role of E2F2 in regulating cellular proliferation.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

E2F2 represses cell cycle regulators to maintain quiescence

Infante

Laresgoiti²,

Fernández-Rueda³

et al. 2008

Cell Cycle

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E2F transcription factors control diverse biological processes through regulation of target gene expression. However, the mechanism by which this regulation is established, and the relative contribution of each E2F member are still poorly defined. We have investigated the role of E2F2 in regulating cellular proliferation. We show that E2F2 is required for the normal G 0 /G 1 phase because targeted disruption of the E2F2 gene causes T cells to enter S phase early and to undergo accelerated cell division. A large set of E2F target genes involved in DNA replication and cell cycle progression (such as Mcm's, cyclins and Cdc2a) that are silent in G 0 and typically transcribed late in G 1 phase are already actively expressed in quiescent T cells and MEFs lacking E2F2. The classic E2F activators, E2F1 and E2F3, are largely dispensable for this process because compound loss of E2F1 -/-and E2F2 -/-produces a comparably shortened G 0 /G 1 phase, with early S phase entry. Likewise, shRNA knockdown of E2F3 does not alter significantly the E2F2 -/-phenotype. Chromatin immunoprecipitation analysis indicates that in wild-type cells the promoters of the aberrantly early-transcribed genes are occupied by E2F2 in G 0 , suggesting a direct role for E2F2 in transcriptional repression. We conclude that E2F2 functions to transcriptionally repress cell cycle genes to establish the G 0 state.

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“…Thus the roles of E2F2 in either suppressing or promoting cell growth may be tissue specific. Indeed, E2F2 has been shown to have a tissue-restricted role in erythropoiesis and neuronal differentiation (13,31), and several studies have suggested that E2F2 may also be involved in apoptosis (43) although this still needs to be confirmed.One of the most paradigmatic models of cell-cycle progression is liver regeneration. Following partial hepatectomy (PH), 90 -95% of the remaining parenchymal cells synchronously reenter the cell cycle to begin regeneration (39).…”

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A role for transcription factor E2F2 in hepatocyte proliferation and timely liver regeneration

Delgado

Fresnedo²,

Iglesias

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Present evidence suggests that E2F2 may act both as a suppressor and promoter of proliferation, depending on the cellular context. We used a loss-of-function mutant mouse model to investigate the function of E2F2 in liver regeneration after partial hepatectomy, a paradigm of cell-cycle progression. Liver mass recovery and histology were examined over 9 days in 70% hepatectomized E2F2Ϫ/Ϫ and wild-type animals. Transcriptome analysis was performed in quiescent and 48-h regenerating liver samples. TIGR MultiExperiment Viewer was used for the statistical analysis of microarray data, significance was determined by Fischer, and P values were adjusted applying BenjaminiHochberg multiple-testing correction. We show that E2F2 is required for adult hepatocyte proliferation and for timely liver regeneration, as disruption of the E2F2 gene in hepatocytes leads to a reduced rate of S-phase entry and to delayed liver regeneration. Transcriptome analysis followed by ontological classification of differentially expressed genes and gene-interaction network analysis indicated that the majority of genes involved in normal liver regeneration were related to biosynthetic and catabolic processes of all major biomolecules as well as cellular location and intracellular transport, confirming the complex nature of the regeneration process. Remarkably, transcripts of genes included in functional categories that are crucial for cell cycle, apoptosis and wound-healing response, and fibrosis were absent in the transcriptome of posthepatectomized E2F2 Ϫ/Ϫ mice. Our results indicate that the transcriptional activity of E2F2 contributes to promote adult hepatocyte proliferation and liver regeneration. cell cycle; transcriptome; liver repair; partial hepatectomy THE E2F TRANSCRIPTION FACTORS are key regulators of cell proliferation and rate-limiting factors in the S-phase entry, as they regulate the expression of many genes involved in the G 1 /S transition. According to the most accepted model of cell-cycle control, unphosphorylated retinoblastoma tumor suppressor protein (pRb) binds to E2F in G 0 /G 1 , forming a complex that actively represses E2F-responsive genes. In late G 1 pRb is inactivated because of phosphorylation by cyclin-dependent kinases, releasing free E2Fs that activate the expression of their target genes (4,12,42).The E2F family is presently composed of nine members encoded by eight different genes (E2F1-8) (4,12,20,42).Members of E2F family can be classified into "activators" (E2F1-3a) and "repressors" (E2F3b-8). Activator E2Fs are considered potent activators of transcription and positive regulators of the cell cycle. Overexpression of any of these activator E2Fs is sufficient to promote G 1 /S transition and DNA replication in immortalized, quiescent rodent fibroblasts in the absence of growth factors (23). However, there is increasing evidence that they may also act as transcriptional repressors (2,7,18,28). E2F1 seems to act both as an oncogene and as a tumor suppressor in the liver (6) but was found not to be essential f...

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E2F2 converts reversibly differentiated PC12 cells to an irreversible, neurotrophin-dependent state

Cited by 21 publications

References 49 publications

NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number

NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number

E2F2 represses cell cycle regulators to maintain quiescence

A role for transcription factor E2F2 in hepatocyte proliferation and timely liver regeneration

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