Inhibition of protein phosphatases induces IGF‐1‐blocked neurotrophin‐insensitive neuronal apoptosis

Fernández-Sánchez, Maria Teresa; García-Rodríguez, Armando; Trelles, Ramón Dı́az; Novelli, Antonello

doi:10.1016/s0014-5793(96)01192-1

Cited by 46 publications

(28 citation statements)

References 45 publications

(66 reference statements)

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“…Although we did not address the issue of an involvement of phosphatases in our model, okadaic acid (OA), a serine/threonine phosphatase inhibitor has been demonstrated to induce death of CGNs and hippocampal neurons (Fernandez-Sanchez et al, 1996;Runden et al, 1998). In hippocampal neurons, OAinduced cell death is accompanied by sustained activation of ERK.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 1 Inhibits Extracellular Signal-Regulated Kinase to Promote Neuronal Survival via the Phosphatidylinositol 3-Kinase/Protein Kinase A/c-Raf Pathway

Subramaniam¹,

Shahani²,

Strelau³

et al. 2005

J. Neurosci.

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Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 1 Inhibits Extracellular Signal-Regulated Kinase to Promote Neuronal Survival via the Phosphatidylinositol 3-Kinase/Protein Kinase A/c-Raf Pathway

Subramaniam¹,

Shahani²,

Strelau³

et al. 2005

J. Neurosci.

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“…In a more recent report [54], FernandezSanchez et al suggested that in primary cultures of rat cerebellar granule neurons, inhibition of PP-2A but not PP-1 leads to apoptosis since 5 nM but not 100 nM okadaic acid induces DNA fragmentation. In both cases, however, it was not determined whether 100 µM microcystin can actually inhibit PP-1 or whether 5 nM okadaic acid can inhibit PP-2A [48,54]. We briefly reported that PP-1 is important in regulating the apoptotic program in the lens system [71].…”

Section: Discussionmentioning

confidence: 99%

Okadaic acid‐induced lens epithelial cell apoptosis requires inhibition of phosphatase‐1 and is associated with induction of gene expression including p53 and bax

Fass

Huizar

et al. 1998

European Journal of Biochemistry

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It is well established that phosphorylation and dephosphorylation are key cellular events which regulate important metabolic activities such as gene expression, cell cycle progression, and apoptosis. The polyether fatty acid, okadaic acid has been shown previously to activate apoptosis in a variety of cell lines. Although this marine sponge toxin is known to inhibit protein phosphatase (PP)-2A and PP-1, it is not certain in most cases whether inhibition of PP-1 or PP-2A is necessary to activate apoptosis. Furthermore, it is not clear how inhibition of these phosphatases leads to apoptosis. Here we present evidence that inhibition of PP-2A by okadaic acid does not activate apoptosis in the lens system. However, when PP-1 is inhibited by okadaic acid, rabbit lens epithelial cells undergo rapid apoptosis. Associated with this process is the several-fold up-regulation of the tumor suppressor gene p53 and the pro-apoptotic gene bax at both mRNA and protein levels. Analyses of the temporal pattern of expression of the two genes reveal that the up-regulation is maximized in a few hours after treatment with okadaic acid, when the majority of the treated cells become committed to apoptosis. A brief treatment of the cells with a protein synthesis inhibitor can abolish okadaic acid-induced up-regulation of both P53 and Bax proteins. Concomitant with this inhibition, okadaic acid-induced apoptosis is also temporarily blocked. These results suggest that okadaic acid-induced expression of p53, bax, and other genes are necessary for the activation of the apoptotic programs in lens systems.Keywords : apoptosis; p53 ; bax ; phosphatase-1; lens.Apoptosis is a distinct form of cell death regulated by internal genetic programs [1,2]. The morphological changes associated with apoptosis include blebbing of cytoplasmic membranes, condensation of nucleoplasm and cytoplasm, and fragmentation of the dying cell into apoptotic bodies which are phagocytosed by neighboring cells [3,4]. The biochemical hallmarks of apoptosis are marked by DNA fragmentation into nucleosomal fragments [4,5], activation of the interleukin-1β-converting enzyme family of proteases [6], and cleavage of various substrates of that family of proteases such as poly(ADPribose) polymerase [7,8] and nuclear lamin [9].Apoptosis normally occurs as a physiological process during certain stages of animal development or during tissue homeostasis in an adult organism [10,11]. It can also be triggered by various external signals such as hormone [4], γ-irradiation [12] and withdrawal of growth factors [13] and other factors (reviewed in [2]). Normal physiological apoptosis helps to remove

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“…PP-1 promotes survival through regulation of p53 and other targets It has been well documented that inhibition of PP-1 or/and PP-2A by the marine algae toxins, okadaic acid and calyculin A, induces apoptosis of various types of cells (Boe et al, 1991;Ishida et al, 1992;Mellgren et al, 1993;Kiguchi et al, 1994;Weller et al, 1995;Fernandez-Sanchez et al, 1996;Morana et al, 1996;Sheikh et al, 1996;Yan et al, 1997;Li et al, 1998Li et al, , 2001aGarcia et al, 2003). However, why inhibition of PP-1 or/and PP-2A leads to apoptosis remains largely unknown.…”

Section: Dephosphorylation Of P53 Displays Strong Impact On Its Functmentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

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We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

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Inhibition of protein phosphatases induces IGF‐1‐blocked neurotrophin‐insensitive neuronal apoptosis

Cited by 46 publications

References 45 publications

Insulin-Like Growth Factor 1 Inhibits Extracellular Signal-Regulated Kinase to Promote Neuronal Survival via the Phosphatidylinositol 3-Kinase/Protein Kinase A/c-Raf Pathway

Insulin-Like Growth Factor 1 Inhibits Extracellular Signal-Regulated Kinase to Promote Neuronal Survival via the Phosphatidylinositol 3-Kinase/Protein Kinase A/c-Raf Pathway

Okadaic acid‐induced lens epithelial cell apoptosis requires inhibition of phosphatase‐1 and is associated with induction of gene expression including p53 and bax

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

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