Alternative roles for Cdk5 in learning and synaptic plasticity

Hawasli, Ammar H.; Bibb, James A.

doi:10.1002/biot.200700093

Cited by 49 publications

(42 citation statements)

References 60 publications

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“…Although CDK5 is ubiquitously expressed, the high neuronal expression of the p35 and p39 implies that CDK5 exerts its major physiologic function in a specific repertoire of tissues, such as the central nervous system. Indeed, previous studies indicated that CDK5 plays a role in a variety of pathologic and physiologic processes associated with neuronal migration during brain development, synaptic activity in mature neurons, and regulation of neuronal cell survival and death (23)(24)(25). Interestingly, these CDK5-dependent functions are unrelated to the regulation of the cell cycle as seen in other CDKs.…”

Section: Introductionmentioning

confidence: 99%

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cao

Zhou

Zhang

et al. 2015

Clinical Cancer Research

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Purpose: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown.Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and realtime PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth.Results: CDK5 level was significantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis.Conclusions: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells.

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Section: Introductionmentioning

confidence: 99%

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cao

Zhou

Zhang

et al. 2015

Clinical Cancer Research

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“…We used two loss-of-function approaches to show that Cdk5 activity is essential for cLTP-induced TrkB surface insertion: pharmacological inhibition of Cdk5 and siRNA knock-down of Cdk5 levels. Cdk5 has been shown to play an important role in synaptic plasticity (Angelo et al, 2006;Cheung et al, 2006;Hawasli and Bibb, 2007). Recently, it has been reported that Cdk5 could directly phosphorylate TrkB and is involved in BDNF-stimulated dendritic growth in hippocampal neurons (Cheung et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface

Zhao

Sheng

Huang

et al. 2009

Journal of Cell Science

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Activity-dependent insertion of tyrosine kinase receptor type 2 (TrkB receptor) into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons; however, the detailed cellular and molecular mechanisms underlying this process are still unclear. In our study, we developed a fluorescence ratiometric assay for surface TrkB receptors to investigate the mechanisms of recruitment of TrkB to the plasma membrane following chemical long-term potentiation (cLTP) induction. We found that, in hippocampal neurons, the effect of cLTP-induced TrkB surface-recruitment occurred predominantly on neurites with rapid kinetics (t1/2 of ∼2.3 minutes) and was dependent on an intact cytoskeleton structure. Mutagenesis studies revealed that the juxtamembrane domain of TrkB is necessary and sufficient for its activity-dependent insertion into the plasma membrane. Moreover, we found that the phosphorylation of TrkB receptor at the Ser478 site by cyclin-dependent kinase 5 (Cdk5) is essential for cLTP-induced TrkB insertion into the neuronal surface. Finally, the degree of cLTP-induced TrkB surface-recruitment is higher in postsynaptic regions, which provides a potential mechanism for rapid enhancement of postsynaptic sensitivity to incoming BDNF signaling. Our studies provide new insights regarding neuronal activity-dependent surface delivery of TrkB receptor, which will advance our understanding of the modulatory role of TrkB in synaptic plasticity.

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“…Consistent with this, many Cdks are expressed in terminally differentiated neurons (57)(58)(59)(60)(61), and furthermore, Cdk5, the sole non-cyclin-activated member of the Cdk family, has been shown to regulate synaptic plasticity and learning (62)(63)(64)(65)(66)(67). Notably, neither SU-9516 nor its primarily characterized target, Cdk2, has been implicated in synaptic plasticity or learning.…”

Section: Conservation Of Neural Substrates Of Learning Between Zebrafmentioning

confidence: 92%

Chemical modulation of memory formation in larval zebrafish

Wolman

Jain

Liss

et al. 2011

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

183

272

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Whole organism-based small-molecule screens have proven powerful in identifying novel therapeutic chemicals, yet this approach has not been exploited to identify new cognitive enhancers. Here we present an automated high-throughput system for measuring nonassociative learning behaviors in larval zebrafish. Using this system, we report that spaced training blocks of repetitive visual stimuli elicit protein synthesis-dependent long-term habituation in larval zebrafish, lasting up to 24 h. Moreover, repetitive acoustic stimulation induces robust short-term habituation that can be modulated by stimulation frequency and instantaneously dishabituated through cross-modal stimulation. To characterize the neurochemical pathways underlying short-term habituation, we screened 1,760 bioactive compounds with known targets. Although we found extensive functional conservation of short-term learning between larval zebrafish and mammalian models, we also discovered several compounds with previously unknown roles in learning. These compounds included a myristic acid analog known to interact with Src family kinases and an inhibitor of cyclin dependent kinase 2, demonstrating that high-throughput chemical screens combined with high-resolution behavioral assays provide a powerful approach for the discovery of novel cognitive modulators.acoustic startle response | sensorimotor gating A ll organisms, from protozoa to humans, use nonassociative habituation learning as a means to update behavioral responses to sensory input based on recent stimulation history (1). Considered a simple form of learning, habituation reflects a suppressed behavioral response to repeated inconsequential stimulation and serves as a mechanism by which the nervous system filters irrelevant stimuli. Defective habituation not only is indicative of a learning deficit, but also is prevalent in neuropsychiatric conditions, such as schizophrenia, attention deficit hyperactivity disorder, posttraumatic stress disorder, and drug addiction (2-5). Numerous assays have shown that the parameters and rules for habituation learning are similar across phyla (6-9), suggesting conservation of the underlying molecular mechanisms. For example, training session design and stimulation frequency is predictive of the time scale of memory retention. Massed exposure to repeated stimulation at short interstimulus intervals (ISIs) elicits an acquisition of learned information with short-term recall memory, indicated by a change in behavior that does not persist for long after the repeated stimulation is terminated. In contrast, a distributed training protocol with multiple training sessions consisting of stimulation at longer ISIs and rest periods between training blocks induces the acquisition and storage of learned behavior that is capable of being recalled for a more extended period. Thus, intrasession, short-term habituation represents working memory, whereas intersession, long-term habituation includes the storage and retrieval of memory.Existing strategies to measure vertebrate lea...

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Alternative roles for Cdk5 in learning and synaptic plasticity

Cited by 49 publications

References 60 publications

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Cyclin-Dependent Kinase 5 Decreases in Gastric Cancer and Its Nuclear Accumulation Suppresses Gastric Tumorigenesis

Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface

Chemical modulation of memory formation in larval zebrafish

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