γCaMKII Shuttles Ca2+/CaM to the Nucleus to Trigger CREB Phosphorylation and Gene Expression

Ma, Hongxia; Groth, Rachel D.; Cohen, Samuel M.; Emery, John F.; Li, Boxing; Hoedt, Esthelle; Zhang, Guoan; Neubert, Thomas A.; Tsien, Richard W.

doi:10.1016/j.cell.2014.09.019

Cited by 232 publications

(313 citation statements)

References 97 publications

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“…Additional CaM kinases and CaMKIV form a CaMK cascade within the nucleus. Neuronal activity and Ca 2+ /CaM drive CaMKK to phosphorylate and activate nuclear CaMKIV, which phosphorylates CREB and CREB-binding protein (39). In the present study, a notable finding was that the expression and activity of CaM in the MCAO group was significantly increased, in contrast to the sham and EA groups.…”

Section: Discussioncontrasting

confidence: 42%

Electroacupuncture improves cognitive ability following cerebral ischemia reperfusion injury via CaM-CaMKIV-CREB signaling in the rat hippocampus

Zhang

Lin

Tao

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the effect of electroacupuncture (EA) on cognitive deficits, and the underlying mechanism following cerebral ischemia-reperfusion (I/R) via the calmodulin (CaM)-calmodulin-dependent protein kinase type IV (CaMKIV)-cyclic adenosine monophosphate response elements binding protein (CREB) intracellular signaling pathway in the hippocampus. In total, 45 adult female Sprague-Dawley rats were randomly divided into three groups, namely the sham group, the middle cerebral artery occlusion (MCAO) group and the MCAO + EA group. Rats in the MCAO and MCAO + EA groups were modeled for post-stroke cognitive impairment. EA was performed at the Baihui and Shenting acupuncture points for 30 min/day for one week in the MCAO + EA group. Behavioral testing was analyzed using a step-down apparatus, while 2,3,5-triphenyl tetrazolium chloride was used to detect the infarct volume and lesion size. In addition, CaM activity was assessed by cyclic nucleotide-dependent phosphodiesterase analysis, and the protein expression levels of CaM, CaMKIV, phosphorylated (p)-CaMKIV, CREB and p-CREB were analyzed by western blot analysis. The cerebral I/R injured rat model in the MCAO group was established successfully with regard to the infarct volume and neuronal lesion size, as compared with the sham group. EA was demonstrated to effectively improve the cognitive ability, as measured by the step-down apparatus test, and decrease the infarct volume when compared with the MCAO group (P<0.05). The step-down apparatus test for the EA-treated rats revealed improved learning and reduced memory impairment when compared with the MCAO group. Furthermore, CaM activity and CaM protein expression levels in the MCAO + EA group were lower compared with those in the MCAO group (P<0.05). By contrast, the protein expression levels of CaMKIV, p-CaMKIV, CREB and p-CREB were significantly reduced in the MCAO group when compared with the sham group (P<0.05), although the expression levels increased following EA treatment when compared with the MCAO group (P<0.05). Therefore, cognitive repair benefited from EA, and the main intracellular signaling pathway in the hippocampus was mediated by CaM-CaMKIV-CREB. EA effectively inhibited the expression and activity of CaM, while further enhancing the expression of CaMKIV and CREB, and their associated phosphorylated functions.

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Section: Discussioncontrasting

confidence: 42%

Electroacupuncture improves cognitive ability following cerebral ischemia reperfusion injury via CaM-CaMKIV-CREB signaling in the rat hippocampus

Zhang

Lin

Tao

et al. 2016

Experimental and Therapeutic Medicine

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“…S1C, top panels), or KN-93, a calcium-dependent calmodulin-dependent kinase II inhibitor (Supplemental Fig. S1C, bottom panels), consistent with CAMKII activation of CREB (Ma et al 2014). Calmidazolium also blocked the early increase in MITF mRNA expression in response to glutamine deprivation (Supplemental Fig.…”

Section: Glutamine Limitation Suppresses Mitfmentioning

confidence: 68%

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

et al. 2017

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The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammationmediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.

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“…S1). These data, together with the previous reports regarding the role of CaMKII in CREB phosphorylation (37) and the characteristic subtype-specific nuclear translocation of the kinase (38,39), show that CaMKII may not contribute to CREB dephosphorylation.…”

Section: Overexpression Of Htau In Hippocampal Neurons Induces Memorymentioning

confidence: 75%

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

Yin

Gao

Wang

et al. 2016

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

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Intracellular accumulation of wild-type tau is a hallmark of sporadic Alzheimer's disease (AD), but the molecular mechanisms underlying tau-induced synapse impairment and memory deficit are poorly understood. Here we found that overexpression of human wild-type full-length tau (termed hTau) induced memory deficits with impairments of synaptic plasticity. Both in vivo and in vitro data demonstrated that hTau accumulation caused remarkable dephosphorylation of cAMP response element binding protein (CREB) in the nuclear fraction. Simultaneously, the calcium-dependent protein phosphatase calcineurin (CaN) was up-regulated, whereas the calcium/ calmodulin-dependent protein kinase IV (CaMKIV) was suppressed. Further studies revealed that CaN activation could dephosphorylate CREB and CaMKIV, and the effect of CaN on CREB dephosphorylation was independent of CaMKIV inhibition. Finally, inhibition of CaN attenuated the hTau-induced CREB dephosphorylation with improved synapse and memory functions. Together, these data indicate that the hTau accumulation impairs synapse and memory by CaN-mediated suppression of nuclear CaMKIV/CREB signaling. Our findings not only reveal new mechanisms underlying the hTau-induced synaptic toxicity, but also provide potential targets for rescuing tauopathies.is the most common neurodegenerative disorder characterized clinically by progressive memory loss (1). The extracellular precipitation of β-amyloid (Aβ) (2), intracellular tau accumulation forming neurofibrillary tangles (3), and profound synapse degeneration are hallmark pathologies in AD brains (4, 5). Studies show that formation of neurofibrillary tangles is positively correlated with the degree of dementia symptoms (6), and the Aβ toxicity needs the presence of tau (7). These data suggest a crucial role of tau accumulation in neurodegeneration and the cognitive impairments in patients with AD. As a cytoskeleton protein, how tau accumulation causes memory deficits is not fully understood.Synapse is the fundamental unit for learning and memory. Dysfunction of synaptic connections is recognized as the cause of memory impairments, and significant synapse loss has been observed in mild cognitive impairment (MCI) and in earlier stages of AD (8). In AD mouse models, synapse impairments appear before the onset of memory deficit (9), whereas amelioration of synapse loss by administration of estradiol preserves cognitive functions (10). Earlier investigations into AD-related synaptic damages have been mainly focused on the toxic effects of Aβ (11). Recently, an emerging role of tau in synaptic impairment has been shown (12). For instance, overexpression of human mutant tau in mice induces synaptic degeneration even in the absence of tangles (13, 14) and reducing endogenous tau in mouse models carrying the mutated amyloid precursor protein (APP) prevents the cognitive deficits and synaptic loss (15).Among many structural or functional proteins involved in synapse development and memory formation, cAMP response element binding protein (CREB) is...

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γCaMKII Shuttles Ca2+/CaM to the Nucleus to Trigger CREB Phosphorylation and Gene Expression

Cited by 232 publications

References 97 publications

Electroacupuncture improves cognitive ability following cerebral ischemia reperfusion injury via CaM-CaMKIV-CREB signaling in the rat hippocampus

Electroacupuncture improves cognitive ability following cerebral ischemia reperfusion injury via CaM-CaMKIV-CREB signaling in the rat hippocampus

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

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