E2F1 induces cell death, calpain activation, and MDMX degradation in a transcription independent manner implicating a novel role for E2F1 in neuronal loss in SIV encephalitis

Strachan, Gordon D.; Koike, Maya A.; Siman, Robert; Hall, D.; Jordan‐Sciutto, Kelly L.

doi:10.1002/jcb.20574

Cited by 20 publications

(28 citation statements)

References 60 publications

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“…L. Jordan-Sciutto et al, 2000). We have also observed decreased expression of a negative regulator of E2F1, murine double minute x/4 (MDMx), in the SIVE brain (Strachan, Koike, Siman, Hall, & Jordan-Sciutto, 2005). …”

Section: Introductionmentioning

confidence: 82%

“…We previously demonstrated decreased MDMx expression and increased cytoplasmic E2F1 expression in the frontal cortex, basal ganglia and hippocampus of SIV-infected macaques with encephalitis (SIVE), and increased cytoplasmic E2F1 expression in HIVE (Strachan et al, 2005). We further showed that cytoplasmic E2F1 in HEK293 cells is associated with calpain activation and transcription-independent degradation of MDMx (Strachan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Calpain-mediated degradation of MDMx/MDM4 contributes to HIV-induced neuronal damage

Colacurcio

Yeager

Kolson

et al. 2013

Molecular and Cellular Neuroscience

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Neuronal damage in HIV-associated Neurocognitive Disorders (HAND) has been linked to inflammation induced by soluble factors released by HIV-infected, and non-infected, activated macrophages/microglia (HIV M/M) in the brain. It has been suggested that aberrant neuronal cell cycle activation determines cell fate in response to these toxic factors. We have previously shown increased expression of cell cycle proteins such as E2F1 and phosphorylated pRb in HAND midfrontal cortex in vivo and in primary neurons exposed to HIV M/M supernatants in vitro. In addition, we also demonstrated have previously shown that MDMx (also referred to as MDM4), a negative regulator of E2F1, was decreased in the brain in a primate model of HIV-induced CNS neurodegeneration. Thus, we hypothesized that MDMx provides indirect neuroprotection from HIV-induced neurodegeneration in our in vitro model. In this report, we found significant reductions in MDMx protein levels in the mid-frontal cortex of patients with HAND. In addition, treatment of primary rat neuroglial cultures with HIV M/M led to NMDA receptor- and calpain-dependent degradation of MDMx and decreased neuronal survival, while overexpression of MDMx conferred partial protection from HIV M/M toxicity in vitro. Further, our results demonstrate that MDMx is a novel and direct calpain substrate. Finally, blocking MDMx activity led to neuronal death in vitro in the absence of toxic stimulus, which was reversed by calpain inhibition. Overall, our results indicate that MDMx plays a pro-survival role in neurons, and that strategies to stabilize and/or induce MDMx can provide neuroprotection in HAND and in other neurodegenerative diseases where calpain activation contributes to neuropathogenesis.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Calpain-mediated degradation of MDMx/MDM4 contributes to HIV-induced neuronal damage

Colacurcio

Yeager

Kolson

et al. 2013

Molecular and Cellular Neuroscience

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“…Some of the mechanism involved in the regulation of calpain activity leading to apoptosis or necrosis. (70). The main conclusion of this study is that overexpression of calpastatin offers partial neuroprotection against excitotoxicity, and, therefore, modulation of the balance between calpains and calpastatin activities offers a potential therapeutic target for the treatment of neurodegenerative pathologies.…”

Section: Role Of Calpain Activation In Neuronal Cell Deathmentioning

confidence: 92%

“…MEF-2 is localized in the nuclei and promotes neuronal cell death (19,24,67). Still another strategy for the development of new drugs to treat AD could be the overexpression of calpastatin, which might prevent tau phosphorylation (70). The downregulation of calpain activity should attenuate degradation as well as phosphorylation of tau.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Involvement of Calpain Activation in Neurodegenerative Processes

et al. 2006

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One of the challenges in the coming years will be to better understand the mechanisms of neuronal cell death with the objective of developing adequate drugs for the treatment of neurodegenerative disorders. Caspases and calpains are among the best-characterized cysteine proteases activated in brain disorders. Likewise, during the last decade, extensive research revealed that the deregulation of calpains activity is a key cytotoxic event in a variety of neurodegenerative disorders. Moreover, interest in the role of calpain in neurodegenerative processes is growing due to implication of the involvement of cdk5 in neurodegenerative diseases. Since calpain inhibitors appear to not only protect brain tissue from ischemia, but also to prevent neurotoxicity caused by such neurotoxins as â-amyloid or 3-nitropropionic acid, the currently available data suggest that calpain and cdk5 play a key role in neuronal cell death. It seems clear that the inappropriate activation of cysteine proteases occurs not only during neuronal cell death, but may also contribute to brain pathology in ischemia and traumatic brain disorders. Pharmacological modulation of calpain activation may, therefore, be useful in the treatment of neurodegenerative disorders. It is possible, although difficult, to develop synthetic inhibitors of cysteine proteases, specifically calpains. The inhibition of calpain activation has recently emerged as a potential therapeutic target for the treatment of neurodegenerative diseases. 135

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“…However, studies have shown that neurons express cell cycle molecules from different phases simultaneously or localized in the ''wrong'' subcellular compartment (Copani et al 2001;Ogawa et al 2003;Strachan et al 2005;Qu et al 2007), and it is hypothesized that this aberrant cell cycle could facilitate PCD.…”

Section: Dna Damage And/or Aberrant Cell Cyclementioning

confidence: 98%

Cell Cycle Activation and CNS Injury

2009

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Although traditionally it was believed that adult neurons have entered a permanent post-mitotic phase, the latest experimental data indicate that cell cycle constituents critically affect normal functions of the adult central nervous system (CNS), as well as contribute to the pathophysiology of both acute and chronic neurodegenerative disorders. Recent study has also suggested that cell cycle pathways are involved in mediating not only neuronal cell death but also glial changes which may play key roles in the pathophysiological mechanisms underlying acute and chronic neurodegenerative disorders. Therefore, therapies that inhibit cell cycle may have robust neuroprotective profiles, particularly after acute insults, by targeting multiple pathogenic mechanisms and could be useful clinically if used with a delivery focused on specific areas and of a limited duration.

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E2F1 induces cell death, calpain activation, and MDMX degradation in a transcription independent manner implicating a novel role for E2F1 in neuronal loss in SIV encephalitis

Cited by 20 publications

References 60 publications

Calpain-mediated degradation of MDMx/MDM4 contributes to HIV-induced neuronal damage

Calpain-mediated degradation of MDMx/MDM4 contributes to HIV-induced neuronal damage

Involvement of Calpain Activation in Neurodegenerative Processes

Cell Cycle Activation and CNS Injury

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