MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts

Gentiletti, Francesca; Mancini, Francesca; D'Angelo, Marco; Sacchi, Ada; Pontecorvi, Alfredo; Jochemsen, Aart G.; Moretti, Fabiola

doi:10.1038/sj.onc.1205137

Cited by 36 publications

(43 citation statements)

References 47 publications

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“…Recently, caspase activities were found to be involved in biological events different from apoptotic death, such as the negative control of erythroid differentiation 23 and the modulation of the MDM2 and MDMX proteins in nonapoptotic cells. 33,34 Our results add evidence for a novel role of caspases, strengthening the concept that this complex net of proteases has been evolutionarily selected to accomplish multiple, different tasks in addition to cell suicide. However, whether the same caspases are involved in apoptotic and nonapoptotic functions through different mechanisms of activation or specificity, or whether caspase-like activities different from the classical apoptosis-associated caspases are responsible for these newly described, nonapoptotic functions need to be evaluated.…”

Section: Erk2 Cleavage Is Required For P53 To Inhibit Cell Proliferationsupporting

confidence: 68%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21 Waf1 , is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

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Section: Erk2 Cleavage Is Required For P53 To Inhibit Cell Proliferationsupporting

confidence: 68%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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“…Several studies reported that MDMX can be ubiquitinated by MDM2 and subsequently degraded through the proteasome after a toxic treatment in various cell lines. 35,36 Interestingly, Gentiletti et al 37 proposed that MDMX was processed by caspase-3 and subsequently degraded by the proteasome. Therefore, caspase-3 might be responsible in part for MDMX protein loss in some conditions, but not all as GLU and APP-Ab treatments do not activate caspase-3 ( Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

et al. 2007

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MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid b precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.

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“…Although the identities of the damage sensors remain unknown, the molecular entities responsible for transducing the damage signals to specific effectors are relatively well characterized. For example, one of its roles is to act as a tumor suppressor protein that senses DNA damage and acts as a guardian of genome stability (Chernova et al, 1995;Blaise et al, 2001;Gentiletti et al, 2002). In some cases, p53 becomes a molecular signature based on the type of cancer (Hussain et al, 2000).…”

Section: Role Of P53 In Uv Irradiation-induced Dna Damagementioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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MDMX stability is regulated by p53-induced caspase cleavage in NIH3T3 mouse fibroblasts

Cited by 36 publications

References 47 publications

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

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