Neuronal Cyclin-Dependent Kinase 5 Activity Is Critical for Survival

Tanaka, Teruyuki; Veeranna,; Ohshima, Toshio; Rajan, Prithi; Amin, Niranjana D.; Cho, Andrew; Sreenath, Taduru; Pant, Harish C.; Brady, Roscoe O.; Kulkarni, Ashok B.

doi:10.1523/jneurosci.21-02-00550.2001

Cited by 77 publications

(91 citation statements)

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“…We found that Cdk5 activity was up-regulated in proportion to an increased level of p35 protein but was not affected by an increased level of Cdk5 protein. Our previous report has also demonstrated that Cdk5 activity in TgCdk5 mouse brain was lower than in wild-type mouse brain when the activity was measured by using Cdk5 immunoprecipitates (17), suggesting that Cdk5 overexpression results in an increased level of monomeric Cdk5 if p35 level is not increased. These results indicated that the level of p35 protein is a rate-limiting factor for Cdk5 activity.…”

Section: Discussionmentioning

confidence: 94%

“…To examine the expression profile of the transgene under the regulatory control of the 1.2-kb p35 promoter in vivo, a double transgenic mouse (Tgp35;p35Ϫ͞Ϫ) was further generated by using a two-step breeding strategy by which the Tgp35 mouse was regenerated in an endogenous p35-null background. The other mouse models used in this study included p35ϩ͞Ϫ, p35Ϫ͞Ϫ, Cdk5ϩ͞Ϫ, and a transgenic mouse with neuronal overexpression of Cdk5 (TgCdk5) (9,16,17). Genotypes of these mice were determined by performing either Southern blot analysis or PCR on genomic DNA isolated from the tail biopsies.…”

Section: Methodsmentioning

confidence: 99%

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Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Takahashi

Ohshima

Cho

et al. 2005

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

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Cocaine, a drug of abuse, increases synaptic dopamine levels in the striatum by blocking dopamine reuptake at axon terminals. Cyclindependent kinase 5 (Cdk5) and its activator p35, proteins involved in phosphorylation of substrates in postmitotic neurons, have been found to be up-regulated after chronic exposure to cocaine. To further examine the effects of Cdk5 and p35 induction on striatal dopamine signaling, we generated two independent transgenic mouse lines in which Cdk5 or p35 was overexpressed specifically in neurons. We report here that increased Cdk5 activity, as a result of p35 but not of Cdk5 overexpression, leads to attenuation of cocaine-mediated dopamine signaling. Increased Cdk5-mediated phosphorylation of dopamine and cAMP-regulated phosphoprotein, molecular mass 32 kDa (DARPP-32) at Thr-75, was accompanied by decreased phosphorylation of DARPP-32 at Thr-34. Increased Cdk5-mediated phosphorylation of extracellular signalregulated kinase kinase 1 at Thr-286 was accompanied by decreased activation of extracellular signal-regulated kinase 1͞2. These effects contributed to attenuation of cocaine-induced phosphorylation of cAMP response element-binding protein as well as a lesser induction of c-fos in the striatum. These results support the idea that Cdk5 activity is involved in altered gene expression after chronic exposure to cocaine and hence impacts the long-lasting changes in neuronal function underlying cocaine addiction.cocaine addiction ͉ phosphorylation ͉ striatum C ocaine increases synaptic dopamine levels in the striatum and alters gene expression in the dopaminoceptive neurons by activating intracellular pathways that propagate the initial signal from the dopamine D1 receptor to the nucleus (1). Chronic exposure to cocaine up-regulates several transcription factors, resulting in the long-lasting changes in gene expression that are thought to underlie neuronal adaptations in cocaine addiction (2). ⌬FosB, identified as such a transcription factor (3), has been shown to enhance the behavioral responsiveness of animals to cocaine (4, 5). Therefore, identification of the target genes that are regulated by ⌬FosB induction is expected to contribute to a greater understanding of the molecular mechanism underlying cocaine addiction. Recently, chronic treatment of animals with cocaine has been shown to up-regulate the expression of cyclin-dependent kinase 5 (Cdk5) and its activator p35 in the striatum through the induction of ⌬FosB (6, 7).Cdk5 is a member of the Cdk family of serine͞threonine kinases. Unlike other Cdks that are major regulators of cell-cycle progression, Cdk5 is mainly involved in phosphorylation of substrates in postmitotic neurons (8). The neuronal specificity of Cdk5 activity is achieved through the association with its activators, either p35 or p39, which are predominantly expressed in postmitotic neurons (8). In addition to the essential role of Cdk5 in brain development (9, 10), it has also been implicated in dopaminergic transmission in postnatal brain (11,12). Inhibition of ...

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Takahashi

Ohshima

Cho

et al. 2005

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

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“…Cdk5Ϫ/Ϫ Mouse Brain-Previous studies have shown that neuronal Cdk5 activity is necessary for survival and nervous system development (29,30,46). Phospholipid kinases, the phosphoinositide kinases, are responsible for the phospholipid phosphorylation.…”

Section: Reduced Brain Lipid Phosphorylation and Pi3k Activity Inmentioning

confidence: 99%

“…The absence of Cdk5 activity in the Cdk5 knockout mouse causes embryonic-lethal and induces cortical and cerebellar abnormalities and increased cortical apoptosis (24,30). The phenotype is rescued when Cdk5 (driven by a neuron-specific promoter, p35) is overexpressed in a transgenic Cdk5 knockout mouse host, suggesting a key role of neuronal Cdk5 activity in sustaining neuronal survival (29). Furthermore, we have also shown that Cdk5 can modulate neuronal survival by phosphorylating and inhibiting c-Jun Nterminal kinase 3 kinase activity, thereby blocking this apoptotic pathway (30).…”

Section: Fig 6 Cdk5 Involved In Neuregulin-induced Phosphorylation mentioning

confidence: 99%

“…The p35 knockout mice are viable and fertile (26,27), with fewer severe abnormalities of laminar structures in the cerebral cortex, compared with Cdk5 null mice (28). Recent studies on Cdk5 null mice expressing transgenic Cdk5, regulated by a p35 promoter to ensure specific expression in brain neurons (TgKO), were rescued and exhibited the wild type phenotype (29). This suggests that neuronal survival (and host survival) is dependent upon Cdk5 activity.…”

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confidence: 99%

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Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Jaffe

et al. 2003

Journal of Biological Chemistry

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144

119

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The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5؊/؊ mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.Cyclin-dependent kinase 5 (Cdk5) 1 is a serine/threonine kinase, which is predominantly expressed in postmitotic neurons (1). Cdk5 kinase activity requires association with its neuronspecific activators, p35 and p39. Cdk5 kinase activity is essential for neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (2-4). Recently, Cdk5 has been suggested as contributing to the control of neuronal positioning in Reelin signaling during neural development (5) and to mediate neuronal guidance by regulating semaphorin-3A with Fyn kinase (6). Cdk5 and p35 have recently also been shown to regulate presynaptic and postsynaptic activity by phosphorylating Munc-18, amphiphysin, and the NR2A subunit of the N-methyl-D-aspartate receptor (7-11). Cdk5 activity also regulates dopamine signaling by phosphorylating DARPP-32 protein (12) and has been shown to up-regulate the expression of acetylcholine receptor at the neuromuscular junction (13). These studies indicate that Cdk5 is a multifunctional protein kinase in the central nervous system. Cdk5 has been implicated in both cell survival and programmed cell death in neuronal and nonneuronal systems (14,15). Cells induced to apoptosis by exogenous signals such as staurosporin display increased Cdk5 activity (16,17). Recently, Cdk5 in association with p25, a truncated form of p35, has been thought to be deregulated to produce hyperphosphorylated tau protein and to disrupt the neuronal cytoskeleton, and it may be involved in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral secrosis, Parkinson's disease, and Niemann-Pick disease (18 -23). On the other hand, Cdk5 may also be involved in neuronal survival. Cdk5 knockout mice exhibit a unique phenotype with perinatal mortality, associated with extensively disrupted cerebral cortical layering due to abnormal neuronal migration, absence of cerebella foliation, and degeneration of neurons...

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Overview: Engineering Transgenic Constructs and Mice

2009

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Cell biology research encompasses everything from single cells to whole animals. Recent discoveries concerning particular gene functions can be applied to the whole animal for understanding genotype‐phenotype relationships underlying disease mechanisms. For this reason, genetically manipulated mouse models are now considered essential to correctly understand disease processes in whole animals. This unit reviews the basic mouse technologies used to generate conventional transgenic mice, which represent a gain‐of‐function approach. First, an overview of transgenic construct design is presented. This unit then explains basic strategies for the identification and establishment of independent transgenic mouse lines, followed by comments on historical and emerging techniques. It then describes typical problems that are encountered when researchers start to generate transgenic mice. Curr. Protoc. Cell Biol. 42:19.10.1‐19.10.9. © 2009 by John Wiley & Sons, Inc.

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Neuronal Cyclin-Dependent Kinase 5 Activity Is Critical for Survival

Cited by 77 publications

References 45 publications

Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Overview: Engineering Transgenic Constructs and Mice

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