Kinase Suppressor of Ras1 Compartmentalizes Hippocampal Signal Transduction and Subserves Synaptic Plasticity and Memory Formation

Shalin, Sara C.; Hernandez, Caterina M.; Dougherty, M. K.; Morrison, Deborah K.; Sweatt, J. David

doi:10.1016/j.neuron.2006.04.029

Cited by 84 publications

(79 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ERK/MAP kinase cascade is important for spatial learning and synaptic plasticity, and its myriad of upstream signals converge once ERK has been activated [25] . In the current study, ERK was activated by PGS32 in primary hippocampal neurons as well as in the mouse hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: The aim of this study was to investigate the cognition-enhancing activity and underlying mechanisms of a triterpenoid saponin (polygalasaponin XXXII, PGS32) isolated from the roots of Polygala tenuifolia Willd. Methods: The Morris water maze was used to evaluate the spatial learning and memory of mice. To detect the basic properties of synaptic transmission and long-term potentiation (LTP) in the dentate gyrus of rats, electrophysiological recordings were made of evoked potentials. Western blotting analysis and immunofluorescence assays were used to determine the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), synapsin I and the expression of brain derived neurotrophic factor (BDNF). Results: When administered at 0.125, 0.5, or 2 mg/kg, PGS32 could significantly prevent scopolamine-induced cognitive impairments in mice. Intracerebroventricular (icv) administration of PGS32 greatly enhanced basic synaptic transmission in the dentate gyrus of rats and induced LTP. In primary hippocampal neurons, as well as in the hippocampus of maze-trained mice, PGS32 activated the mitogen-activated protein (MAP) kinase cascade by promoting phosphorylation of ERK, CREB and synapsin I. The expression of BDNF was also greatly enhanced in the hippocampus. Conclusion: Our findings suggest that PGS32 can improve hippocampus-dependent learning and memory, possibly through improvement of synaptic transmission, activation of the MAP kinase cascade and enhancement of the level of BDNF. Therefore, PGS32 shows promise as a potential cognition-enhancing therapeutic drug.

show abstract

Section: Discussionmentioning

confidence: 99%

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…The MAPK pathway (Figure 1.9 201,202 . KSR was observed to block oncogenic ras transformation when mutated and appears to have no inherent enzymatic activity 203 .…”

Section: The Mapk Pathwaymentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

show abstract

“…Histone acetylation is catalyzed by histone acetyltransferase enzymes, including the CREB-binding protein, whereas deacetylation is catalyzed by HDAC enzymes (Alarcon et al, 2004;Levenson et al, 2004a;Lubin et al, 2005;Roberson et al, 1999;Shalin et al, 2006;Vecsey et al, 2007). In an important breakthrough in the past few years, several groups discovered that HDAC inhibitors enhance LTP in vitro and augment memory formation in vivo (eg, Alarcon et al, 2004;Chwang et al, 2007;Chwang et al, 2006;Fischer et al, 2007;Korzus et al, 2004;Vecsey et al, 2007), thereby implicating these agents as potential therapeutic targets for CNS disorders.…”

Section: Epigenetic Treatment In the Cnsmentioning

confidence: 99%

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Zovkic

Sweatt

2012

Neuropsychopharmacol

168

108

View full text Add to dashboard Cite

One of the most exciting discoveries in the learning and memory field in the past two decades is the observation that active regulation of gene expression is necessary for experience to trigger lasting functional and behavioral change, in a wide variety of species, including humans. Thus, as opposed to the traditional view of 'nature' (genes) being separate from 'nurture' (environment and experience), it is now clear that experience actively drives alterations in central nervous system (CNS) gene expression in an ongoing fashion, and that the resulting transcriptional changes are necessary for experience to trigger altered long-term behavior. In parallel over the past decade, epigenetic mechanisms, including regulation of chromatin structure and DNA methylation, have been shown to be potent regulators of gene transcription in the CNS. In this review, we describe data supporting the hypothesis that epigenetic molecular mechanisms, especially DNA methylation and demethylation, drive long-term behavioral change through active regulation of gene transcription in the CNS. Specifically, we propose that epigenetic molecular mechanisms underlie the formation and stabilization of context-and cue-triggered fear conditioning based in the hippocampus and amygdala, a conclusion reached in a wide variety of studies using laboratory animals. Given the relevance of cued and contextual fear conditioning to post-traumatic stress, by extension we propose that these mechanisms may contribute to post-traumatic stress disorder (PTSD) in humans. Moreover, we speculate that epigenetically based pharmacotherapy may provide a new avenue of drug treatment for PTSD-related cognitive and behavioral function.

show abstract

Kinase Suppressor of Ras1 Compartmentalizes Hippocampal Signal Transduction and Subserves Synaptic Plasticity and Memory Formation

Cited by 84 publications

References 51 publications

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

Role of the pro-survival molecule Bfl-1 in melanoma

Epigenetic Mechanisms in Learned Fear: Implications for PTSD

Contact Info

Product

Resources

About