The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes

Renault, F; Formstecher, Étienne; Callebaut, Isabelle; Junier, Marie‐Pierre; Chneiweiss, Hervé

doi:10.1016/s0006-2952(03)00514-8

Cited by 70 publications

(69 citation statements)

References 44 publications

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“…As such the protective effect against growth factor depletion is carried out by cytoplasmic ERK, whereas the anti-apoptotic response against STI571 takes place in the nucleus. In line with our data, in D2 myeloid cells phosphorylated ERK accumulates in the cytoplasm of phorbol ester-induced pro-apoptotic cells (63), and recent results indicate that PEA-15, a protein that retains activated ERK in the cytoplasm, can prevent tumor necrosis factor ␣-induced apoptosis in astrocytes (64). On the other hand, we show that constitutive ERK activation, irrespective of its localization, is insufficient to prevent apoptosis induced by stimuli such as UV light, probably as a consequence of the apoptogenic response against this type of radiation being primarily unleashed by processes that occur downstream from ERKs.…”

Section: Discussionsupporting

confidence: 92%

Subcellular Localization Determines the Protective Effects of Activated ERK2 against Distinct Apoptogenic Stimuli in Myeloid Leukemia Cells

Ajenjo

Cañón

Sánchez‐Pérez³

et al. 2004

Journal of Biological Chemistry

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ERKs, mitogen-activated protein kinases, are well characterized as key mediators in the conveyance of signals that promote cell survival in cells of hemopoietic origin, a key factor in the upbringing of leukemogenesis. It is also well known that ERKs phosphorylate a wide array of substrates distributed throughout distinct cellular locations such as the nucleus, cytoplasm, and cell periphery, but the relative contribution of these compartmentalized signal components to the overall survival signal generated by activation of ERKs has yet to be established. To this end, we have utilized constitutively activated forms of ERK2, whose expression is restricted to the nucleus or to the cytoplasm, to investigate the consequences of compartmentalized activation of ERK in the survival of chronic myelogenous leukemia cells subjected to distinct apoptogenic stimuli. We show that cytoplasmic ERK2 activity protected against apoptosis caused by prolonged serum starvation, whereas ERK2 activation restricted to the nucleus antagonized apoptosis induced by the Bcr-Abl inhibitor STI571. On the other hand, neither cytoplasmic nor nuclear ERK2 activities were effective in counteracting apoptosis induced by UV light. These results demonstrate that the protective effects of ERK2 against defined apoptogenic stimuli are strictly dependent on the cellular localization where ERK activation takes place. Furthermore, we present evidence suggesting that the complex I B-NF B participates on ERK2-mediated survival mechanisms, in a fashion dependent on the cellular location where ERK2 is active and on the causative apoptogenic stimulus.

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Section: Discussionsupporting

confidence: 92%

Subcellular Localization Determines the Protective Effects of Activated ERK2 against Distinct Apoptogenic Stimuli in Myeloid Leukemia Cells

Ajenjo

Cañón

Sánchez‐Pérez³

et al. 2004

Journal of Biological Chemistry

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“…Phosphorylation of PED by protein kinase C substantially reduces ERK binding, whereas phosphorylation by CamKII has no effect on ERK binding. PED modifies ERK signaling by excluding ERK from the nucleus (12). Considerable evidence suggests that the Raf/MAPK/ERK cascade may regulate microRNA (miRNA) expression (12).…”

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confidence: 99%

“…PED modifies ERK signaling by excluding ERK from the nucleus (12). Considerable evidence suggests that the Raf/MAPK/ERK cascade may regulate microRNA (miRNA) expression (12). miRNAs are small, evolutionarily conserved, noncoding RNAs of 18-25 nucleotides in length that act as negative regulators of genes involved in many fundamental cell processes, such as development, differentiation, proliferation, survival, and death (13).…”

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confidence: 99%

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Romano

Acunzo

Garofalo

et al. 2012

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

150

137

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MicroRNAs (miRNAs) have an important role in the development of chemosensitivity or chemoresistance in different types of cancer. Activation of the ERK1/2 pathway is a major determinant of diverse cellular processes and cancer development and is responsible for the transcription of several important miRNAs. Here we show a link between the ERK1/2 pathway and BIM expression through miR-494. We blocked ERK1/2 nuclear activity through the overexpression of an ERK1/2 natural interactor, the protein PED/PEA15, and we performed a microRNA expression profile. miR-494 was the most down-regulated microRNA after ERK1/2 inactivation. Moreover, we found that miR-494 induced Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance in non–small-cell lung cancer (NSCLC) through the down-modulation of BIM. Elucidation of this undiscovered ERK1/2 pathway that regulates apoptosis and cell proliferation through miR-494 in NSCLC will greatly enhance our understanding of the mechanisms responsible for TRAIL resistance and will provide an additional arm for the development of anticancer therapies.

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“…PEA15, a multifunctional protein that regulates both apoptosis and cell proliferation (Renault et al, 2003), has been found to relocate ERK from the nucleus to the cytoplasm (Formstecher et al, 2001;Renault et al, 2003;Whitehurst et al, 2004), leading to suppression of proliferation. We thus next assessed the location of ERK and phosphorylated (activated) ERK (pERK) in the E1A-expressing cells.…”

Section: Pea15 Is Upregulated In Ovcar-e1a Cells and Sequesters Erk Imentioning

confidence: 99%

Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

et al. 2005

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The adenovirus type 5 gene E1A is known to suppress tumorigenicity by transcriptionally downregulating HER-2/neu (HER2) or by inducing apoptosis. We show here that E1A also suppressed the tumorigenicity of the low-HER2-expressing ovarian cancer cell line OVCAR-3 by decreasing cell proliferation. We further found that the mechanism responsible for this reduced proliferation is the presence of PEA15 (phosphoprotein enriched in astrocytes), which is upregulated by E1A in ovarian cancer; PEA15 promotes translocation of ERK from the nucleus to the cytoplasm, leading to inhibition of ERK-dependent transcription and proliferation. Indeed, siRNA-mediated knockdown of PEA15 expression in OVCAR-3 stable E1A transfectants resulted in a nuclear accumulation of the active form of ERK, followed by an increase in Elk-1 activity, DNA synthesis, and anchorage-independent growth. Finally, PEA15 by itself suppressed colony formation in breast and ovarian cancer cell lines, in which E1A is known to have antitumor activity. We conclude that part of the antitumor effect of E1A in ovarian cancer results from cytoplasmic sequestration of the activated form of ERK by PEA15.

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The multifunctional protein PEA-15 is involved in the control of apoptosis and cell cycle in astrocytes

Cited by 70 publications

References 44 publications

Subcellular Localization Determines the Protective Effects of Activated ERK2 against Distinct Apoptogenic Stimuli in Myeloid Leukemia Cells

Subcellular Localization Determines the Protective Effects of Activated ERK2 against Distinct Apoptogenic Stimuli in Myeloid Leukemia Cells

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

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