Activation of cAMP Response Element-Mediated Gene Expression by Regulated Nuclear Transport of TORC Proteins

Bittinger, Mark; McWhinnie, Elizabeth; Meltzer, Jodi; Iourgenko, Vadim; Latario, Brian; Liu, Xiulin; Chen, Chein Hwa; Song, Chuanzheng; Garza, Dan; Labow, Mark

doi:10.1016/j.cub.2004.11.002

Cited by 222 publications

(261 citation statements)

References 16 publications

(4 reference statements)

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“…In these cells, forskolin (FSK) decreases TORC2 phosphorylation via cAMP-mediated inhibition of salt-inducible kinases, whereas KCl triggers TORC2 dephosphorylation via calcium entry and resultant activation of calcineurin/protein phosphatase 2B. Subsequently, unphosphorylated TORC2 molecules are released from 14-3-3 proteins, and migrate to the nucleus to activate CRE-regulated genes (3,15). By using a pan-TORC antibody to visualize endogenous TORCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity

Kovács

Steullet

Steinmann

et al. 2007

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

169

200

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A key feature of memory processes is to link different input signals by association and to preserve this coupling at the level of synaptic connections. Late-phase long-term potentiation (L-LTP), a form of synaptic plasticity thought to encode long-term memory, requires gene transcription and protein synthesis. In this study, we report that a recently cloned coactivator of cAMP-response elementbinding protein (CREB), called transducer of regulated CREB activity 1 (TORC1), contributes to this process by sensing the coincidence of calcium and cAMP signals in neurons and by converting it into a transcriptional response that leads to the synthesis of factors required for enhanced synaptic transmission. We provide evidence that TORC1 is involved in L-LTP maintenance at the Schaffer collateral-CA1 synapses in the hippocampus.BDNF ͉ calcineurin ͉ cAMP-response element-binding protein ͉ long-term potentiation ͉ memory T ransducers of regulated cAMP-response element-binding protein (CREB) activity (TORCs) are newly discovered coactivators that dramatically increase CREB's transcriptional activity independently of CREB Ser-133 phosphorylation (1, 2). Recently, it has been shown that TORC2 functions as a pancreatic coincidence detector. In insulinoma cells, glucose and gut hormones, via respective activation of L-type calcium channels and the cAMP pathway, synergistically promote the dephosphorylation and the concomitant nuclear translocation of TORC2 (3). In the brain, encoding and storing associative memories requires detection of the coincidence of different input signals and translation of these associations into changes in the number, structure, or function of synapses. Therefore, it appears that short-lived coincidences result in the transcriptional activation of genes encoding factors required for enhanced synaptic transmission. TORCs present two features that neurons could use to create an association: they can detect the coincidence of the two most important second messengers, calcium and cAMP, and they are potent coactivators of CREB, a transcription factor known to drive the expression of genes underlying synaptic plasticity, late-phase long-term potentiation (L-LTP), learning, and memory (4-7).CREB-dependent promoters have been generally thought to respond to various intracellular and extracellular cues by the stimulus-dependent phosphorylation of CREB at Ser-133 and resultant recruitment of the coactivator CREB binding protein (CBP) (5,6,8,9). Modification of CREB at this site often mirrors the activation of neurons, leading to the idea that the expression of plasticity-related genes relies on CREB/CBP interaction. However, some studies revealing a discrepancy between CREB phosphorylation and CREB-mediated gene transcription have challenged this model. For instance, monocular deprivation induces LacZ expression in the visual cortex of cAMP-response element (CRE)-LacZ transgenic mice (10), whereas phosphorylation of CREB at Ser-133 remains static (11). Similarly, the mechanism underlying CREB activation during L...

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Section: Resultsmentioning

confidence: 99%

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity

Kovács

Steullet

Steinmann

et al. 2007

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

169

200

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“…For example, the Crtc2 homolog was shown to regulate gluconeogenesis by integrating calcium and metabolic signaling through calcineurin and AMPK/SIK kinase families (Bittinger et al, 2004;Screaton et al, 2004;Shaw et al, 2005;Fu and Screaton, 2008). In these experiments, Crtc2 transcriptional co-activator function was negatively regulated by phosphorylation at sites including a critical serine171 that mediates cytoplasmic sequestration and/or degradation (Screaton et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

et al. 2009

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Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steadystate Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.

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“…For example, increases in intracellular calcium result in translocation of histone deacetylase 5 (HDAC5) from the nucleus to the cytoplasm in cultured hippocampal neurons [17]. In contrast, increases in intracellular calcium result in nuclear accumulation of human transducer of regulated CREB (TORC) proteins [18] and nuclear factor of activated T-cells (NF-AT) [19]. Thus, a role for calcium in regulating the nuclear import and export dynamics of proteins has been established.…”

Section: Introductionmentioning

confidence: 99%

Nuclear export of BRCA1 occurs during early S phase and is calcium-dependent

Glover-Collins¹,

Thompson²

2008

Cellular Signalling

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Although the breast cancer susceptibility gene 1 (BRCA1) protein is predominantly nuclear, its localization can vary during the cell cycle in response to cellular insults. For example, in S-phase cells, BRCA1 forms subnuclear foci and localizes to the perinuclear region in response to DNA damage. The present study provides evidence that BRCA1 is transiently excluded from the nucleus during the early part of S phase in the absence of DNA damage. The percentage of MCF-7 human breast cancer cells predominantly expressing nonnuclear BRCA1 significantly correlates with the percentage of cells within early S phase. This redistribution of BRCA1 is partially sensitive to leptomycin B, indicating that CRM-1-mediated nuclear export is involved. Similar results were observed with MCF12A nonmalignant human mammary cells. The abilities of BAPTA-AM, an intracellular calcium chelator, to inhibit the change in BRCA1 localization, and of A23187, a calcium ionophore, and of thapsigargin to mimic nuclear exclusion of BRCA1, provide evidence for the involvement of calcium in this process. The calcium-mediated change in BRCA1 localization occurs in several cell lines, indicating that this effect is not cell line specific. BRCA2 localization is not affected by A23187. Furthermore, inhibition of calcium-calmodulin interaction and calciumcalmodulin dependent protein kinase II attenuates the calcium-mediated change in BRCA1 localization. These data suggest that BRCA1 nuclear export can be cell cycle-regulated by a calciumdependent mechanism.

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Activation of cAMP Response Element-Mediated Gene Expression by Regulated Nuclear Transport of TORC Proteins

Cited by 222 publications

References 16 publications

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

Nuclear export of BRCA1 occurs during early S phase and is calcium-dependent

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