Cdk5-Mediated Inhibition of the Protective Effects of Transcription Factor MEF2 in Neurotoxicity-Induced Apoptosis

Gong, Xiaoming; Tang, Xiaoli; Wiedmann, Marcus; Wang, Xuemin; Peng, Junmin; Zheng, Dong; Blair, Leslie A.C.; Marshall, John; Mao, Zixu

doi:10.1016/s0896-6273(03)00191-0

Cited by 244 publications

(288 citation statements)

References 54 publications

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“…28 Cdk5 may mediate neuronal apoptosis through two distinct mechanisms, a cytoplasmic mechanism that leads to cytoskeleton disruption 6 and a nuclear mechanism that interferes with the transcription of prosurvival genes. 68 Since the presence or absence of active Cdk5 does not appear to affect apoptosis or nonapoptotic cell death, the significance of these findings is unclear.…”

Section: Discussionmentioning

confidence: 99%

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Lin

Zakeri

2005

Cell Death Differ

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Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclindependent kinase family that is mostly seen in neurons, does not vary with cell cycle, and is activated in many neurodegenerative disorders and other non-neuronal pathologies, but its relationship to non-neuronal apoptosis is not understood, nor is the control of the activation of Cdk5 by its activators. The most widely studied activator of Cdk5, p35, is cleaved to p25 by calpain, an event that has been linked with activation of Cdk5 and neuronal death. Here we report that calpain-mediated Cdk5/p25 activation accompanies nonneuronal as well as neuronal cell death, suggesting that the p35/calpain/p25/Cdk5 activation sequence is a general feature of cell death. We further demonstrate that Cdk5 can be activated in the absence of p53, Apaf-1, caspase-9, and -3 during cell death, indicating that its activation relates more to cell death than to a specific pathway of apoptosis.

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Section: Discussionmentioning

confidence: 99%

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Lin

Zakeri

2005

Cell Death Differ

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“…However, with signaling that stimulates MEF2 factor trans-activity, the element functioned as an enhancer. It is established that MEF2 factors can activate or repress transcription, depending on associations with its protein interactors (5, 8, 29, 53, 56 -61) and on cell signaling activities (7,15,28,41,51,52,62). One major mechanism of repression involves class IIa histone deacetylases.…”

Section: Discussionmentioning

confidence: 99%

“…MEF2 proteins contribute to the orchestration of skeletal muscle differentiation (6,7) and fiber type programming (8,9), cardiac development and hypertrophy (10,11), and vascular development and smooth muscle proliferation (12)(13)(14). These factors are also involved in excitation-dependent neuron survival (15,16) and synapse formation (17,18). Some MEF2 factors are expressed in immune cells where they control T cell selection and activation and cytokine expression (19,20).…”

mentioning

confidence: 99%

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Ramachandran

et al. 2008

Journal of Biological Chemistry

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MEF2 (myocyte enhancer factor 2) proteins are a small family of transcription factors that play pivotal roles in striated muscle differentiation, development, and metabolism, in neuron survival and synaptic formation, and in lymphocyte selection and activation. Products of the four mammalian MEF2 genes, MEF2A, MEF2B, MEF2C, and MEF2D, are expressed with overlapping but distinct temporospatial patterns. Toward analysis of MEF2A functions and the determinants of its regulated expression, we have mapped and begun studies of the transcriptional control regions of this gene. Heterogeneous 5 -untranslated regions of MEF2A mRNAs result from use of alternative promoters and splicing patterns. The two closely approximated TATA-less promoters are ϳ65 kb upstream of the exon containing the sole initiation codon. Ribonuclease protection and primer extension assays show that each promoter is active in various adult tissues. A canonical MEF2 site overlies the major promoter 1 transcription start site. This element specifically binds MEF2 factors, including endogenous nuclear MEF2A according to chromatin immunoprecipitation studies, and is critical to MEF2A transcription in myocytes. The site exerts reciprocal control of the alternative promoters, silencing promoter 1 and activating promoter 2 under some conditions. Erk5 and p38 MAPK signaling stimulate MEF2A expression by activating both promoters from the MEF2 element. MEF2A transcription is therefore subject to positive or negative regulation by its protein products, depending on signaling activities that influence MEF2 factor trans-activity. The sole MEF2 gene of the cephalochordate amphioxus has a similar regulatory region structure, suggesting that this mode of autoregulatory control is conserved among higher metazoan MEF2 genes.

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“…Cdk5 activation is increased by cleavage of its regulatory protein p35 to p25 in response to neurotoxic insults. 37,38 Given the emerging link between both Cdk5 and tAIF and oxidative stress-induced neuronal cell death, [39][40][41][42] we hypothesized that oxidative stress-induced Cdk5 activation triggers neuronal cell death by inhibiting CHIP-mediated degradation of tAIF. In primary cultured Figure 3 Cdk5 negatively regulates CHIP-mediated tAIF degradation via UPS.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

et al. 2015

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Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIPmediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP S20A , but not CHIP WT , attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.

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Cdk5-Mediated Inhibition of the Protective Effects of Transcription Factor MEF2 in Neurotoxicity-Induced Apoptosis

Cited by 244 publications

References 54 publications

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

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