A Network of Control Mediated by Regulator of Calcium/Calmodulin-Dependent Signaling

Rakhilin, Sergey; Olson, Patricia A.; Nishi, Akinori; Starkova, Natalia; Fienberg, Allen A.; Nairn, Angus C.; Surmeier, D. James; Greengard, Paul

doi:10.1126/science.1099961

Cited by 90 publications

(107 citation statements)

References 22 publications

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“…With regard to miR-128b, it is highly expressed in the frontal cortex and its host gene, regulator of calmodulin signaling (RCS), is essential for mediating dopamine transmission 9 , which in the ILPFC has been shown to be critical for the formation of fear extinction memories 10 . After auditory cued fear conditioning (3 tone-shock pairings) in a standard conditioning chamber (Context A) on day 1, mice were either exposed to a novel context (Context B) for 2 hours (FC-No EXT) or exposed to a strong extinction protocol (EXT, 60 non-reinforced tone exposures (CS) in order to induce complete extinction) in context B.…”

Section: Resultsmentioning

confidence: 99%

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

et al. 2011

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MicroRNAs are small non-coding RNAs that mediate post-transcriptional gene silencing.Here we demonstrate, in C57/Bl6J mice, that fear extinction learning leads to increased expression of the brain-specific microRNA, miR-128b, which disrupts the stability of several plasticity-related target genes and regulates the formation of fear extinction memory. Increased miR-128b activity may therefore serve to facilitate the transition from retrieval of the original fear memory toward the formation of a new fear extinction memory.Nature Neuroscience (Brief Communication)

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Section: Resultsmentioning

confidence: 99%

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

et al. 2011

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“…miR-128-2 is an intragenic miRNA located within the 18th intron of ARPP21 gene. 30 The analysis of ARPP21 gene expression evidences that ARPP21 mRNA is induced, to a similar extent than that of miR-128-2, following mutant p53His175 expression (Figure 1e and Supplementary Figure 1B). Altogether, these findings indicate that mutant p53 protein controls the expression of both miR-128-2 and ARPP21 through a common transcriptional regulatory mechanism.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function

Donzelli¹,

et al. 2011

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p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21 waf1 transcription. p21 waf1 protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance. Cell Death and Differentiation (2012) 19, 1038-1048 doi:10.1038/cdd.2011 published online 23 December 2011 Mutations in the TP53 gene are the most frequent type of gene-specific alterations in human cancers. 1 The majority of cancer-associated mutations in TP53 gene are missense mutations that reside mainly in the exons encoding for p53 DNA-binding domain. 2 These mutations frequently result in full-length mutant p53 proteins incapable of activating p53 target genes and suppressing tumorigenesis. 3 Most TP53 mutations can be classified into two main categories according to their effect on the thermodynamic stability of the p53 protein. 4 These two mutation categories are commonly referred to as DNA-contact and conformational mutations. The first group includes mutations in residues directly involved in DNA binding, such as R248Q and R273H. The second group comprises mutations that cause local (such as R249S and G245S) or global (such as R175H and R282W) conformational distortions.Besides losing their wild-type (wt) activities, mutant p53 proteins have also dominant-negative effects that inactivate wt p53 protein expressed from the remaining wt allele. Moreover, some mutant p53 forms also acquire new oncogenic properties -'gain of function' -that overrule those due to loss of wt p53 activity by gene deletion. 5-7 These properties range from enhanced proliferation in culture and resistance to a variety of anticancer drugs commonly used in the clinical practice, to increased tumorigenicity in vivo. [8][9][10] Recent work indicates that mutant p53 protein can augment in vitro and in vivo cell migration and invasion. 11 Fontemaggi et al. 12 showed that mutant p53 increases also the angiogenic potential of cancer cells by modulating, at the transcriptional level, Id4 expression.The existing knowledge regarding the molecular mechanisms whereby mutant p53 regulates gene expression is still lacking. To date, we can depict the three following molecular scenarios to explain gain-of-function of mutant p53 proteins: (i) mutant p53 binds to the promoter of ...

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“…PKA-dependent phosphorylation of receptors, ion channels, transcription factors, and other proteins accounts for much of the structural and functional plasticity regulated by dopamine (2). Our previous studies that identified and characterized targets of the cAMP/PKA pathway have been critical for understanding the actions of dopamine in MSNs (3,4). For example, the PKA substrate, dopamine and cAMP-regulated phosphoprotein, M r 32 kDa (DARPP-32) has been extensively analyzed and found to amplify dopamine action in MSNs through inhibition of protein phosphatase-1 (PP1).…”

mentioning

confidence: 99%

Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

McAvoy

Zhou

Greengard

et al. 2009

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

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Protein kinase A (PKA)-dependent signaling cascades play an important role in mediating the effects of dopamine and other neurotransmitters in striatal medium spiny neurons. We have identified a prominent striatal PKA substrate as Rap1-GTPase activating protein (Rap1GAP), a negative regulator of Rap1 signaling. Although present throughout the brain, Rap1GAP is enriched in striatal medium spiny neurons and is phosphorylated by PKA at Ser-441 and Ser-499 in response to activation of D1 dopamine receptors. Phosphorylation of Rap1GAP is associated with inhibition of GAP activity, as demonstrated by increased Rap1 activity in striatal neurons. Phosphorylation of Rap1GAP is also associated with increased dendritic spine head size in cultured neurons. These findings suggest that phosphorylation of Rap1GAP by PKA plays an important role in striatal neurons by modulating Rap1 actions.

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A Network of Control Mediated by Regulator of Calcium/Calmodulin-Dependent Signaling

Cited by 90 publications

References 22 publications

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function

Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

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