Multiple oxidative stress-response members of the Adapt78 family

Michtalik, Henry J.; Narayan, Ananth; Bhatt, Nishant; Lin, Hung-Yun; Mulligan, Michael T.; Zhang, Shen Li; Crawford, Dana R.

doi:10.1016/j.freeradbiomed.2004.05.014

Cited by 17 publications

(10 citation statements)

References 32 publications

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“…Levels of RCAN1-1 proteins also increase transiently and contribute to stress adaptation. However, RCAN1-1 protein levels do not increase as much as do RCAN1-4 protein levels and, unlike RCAN1-4 that is induced through mRNA transcription, they seem to be elevated by translational activation [17,23]. During transient adaptation to oxidative stress, a number of protective proteins are thought to be activated by phosphorylating kinases.…”

Section: The Rcan1 Protein Isoforms: Rcan1-1l Rcan1-1s and Rcan1-4mentioning

confidence: 99%

Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease

Ermak

Davies

2013

Free Radical Biology and Medicine

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The RCAN1 gene encodes three different protein isoforms: RCAN1-4, RCAN1-1L, and RCAN1-1S. RCAN1-1L is the RCAN1 isoform predominantly expressed in human brains. RCAN1 proteins have been shown to regulate various other proteins and cellular functions, including calcineurin, glycogen synthase kinase-3β (GSK-3β), the mitochondrial adenine nucleotide transporter (ANT), stress adaptation, ADP/ATP exchange in mitochondria, and the mitochondrial permeability transition pore (mtPTP). The effects of increased RCAN1 gene expression seem to depend both on the specific RCAN1 protein isoform(s) synthesized and on the length of time the level of each isoform is elevated. Transiently elevated RCAN1-4 and RCAN1-1L protein levels, lasting just a few hours, can be neuroprotective under acute stress conditions, including acute oxidative stress. We propose that, by transiently inhibiting the phosphatase calcineurin, RCAN1-4 and RCAN1-1L may reinforce and extend protective stress-adaptive cell responses. In contrast, prolonged elevation of RCAN1-1L levels is associated with the types of neurodegeneration observed in several diseases, including Alzheimer disease and Down syndrome. RCAN1-1L levels can also be increased by multiple chronic stresses and by glucocorticoids, both of which can cause neurodegeneration. Although increasing levels of RCAN1-1L for just a few months has no overtly obvious neurodegenerative effect, it does suppress neurogenesis. Longer term elevation of RCAN1-1L levels (for at least 16 months), however, can lead to the first signs of neurodegeneration. Such neurodegeneration may be precipitated by (RCAN1-1L-mediated) prolonged calcineurin inhibition and GSK-3β induction/activation, both of which promote tau hyperphosphorylation, and/or by (RCAN1-1L-mediated) effects on the mitochondrial ANT, diminished ATP/ADP ratio, opening of the mtPTP, and mitochondrial autophagy. We propose that RCAN1-1L operates through various molecular mechanisms, primarily dependent upon the length of time protein levels are elevated. We also suggest that models analyzing long-term RCAN1 gene overexpression may help us to understand the molecular mechanisms of neurodegeneration in diseases such as Alzheimer disease, Down syndrome, and possibly others.

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Section: The Rcan1 Protein Isoforms: Rcan1-1l Rcan1-1s and Rcan1-4mentioning

confidence: 99%

Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease

Ermak

Davies

2013

Free Radical Biology and Medicine

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“…1. RCAN1 protein inhibits calcineurin [26][27][28][29][30], a calcium-activated protein phosphatase that mediates many cellular functions, especially in the brain where it comprises more than 1% of the total protein and regulates neuronal apoptosis, N-methyl-D-aspartate receptor channels, neurite outgrowth, long-term memory and potentiation, neurotransmitter release, and tau dephosphorylation [30][31][32][33][34]. Under normal conditions, agonists that elevate intracellular calcium lead to activation of calcineurin, which dephosphorylates NF-AT, leading to its nuclear migration and activation of target genes.…”

Section: Introductionmentioning

confidence: 99%

Fish oil improves gene targets of Down syndrome in C57BL and BALB/c mice

et al. 2015

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“…Our laboratory became interested in immunosuppression research due to our studies on the gene RCAN1 / ADAPT78 [10-12], whose protein product (RCAN1) has been found to inhibit calcineurin [13-17]. Calcineurin is a major mediator of calcium signaling and, as mentioned above, a target for effective immunosuppressants such as cyclosporine and FK506.…”

Section: Introductionmentioning

confidence: 99%

Select phytochemicals suppress human T-lymphocytes and mouse splenocytes suggesting their use in autoimmunity and transplantation

et al. 2009

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We have considered a novel “rational” gene targeting approach for treating pathologies whose genetic bases are defined using select phytochemicals. We reason that one such potential application of this approach would be conditions requiring immunosuppression such as autoimmune disease and transplantation, where the genetic target is clearly defined; i.e., interleukin-2 and associated T-cell activation. Therefore, we hypothesized that select phytochemicals can suppress T-lymphocyte proliferation both in vitro and in vivo. The immunosuppressive effects of berry extract, curcumin, quercetin, sulforaphane, epigallocatechin gallate (EGCG), resveratrol, α-tocopherol, vitamin C and sucrose were tested on anti-CD3 plus anti-CD28-activated primary human T-lymphocytes in culture. Curcumin, sulforaphane, quercetin, berry extract and EGCG all significantly inhibited T-cell proliferation, and this effect was not due to toxicity. IL-2 production was also reduced by these agents, implicating this important T-cell cytokine in proliferation suppression. Except for berry extract, these same agents also inhibited mouse splenic T-cell proliferation and IL-2 production. Subsequent in vivo studies revealed that quercetin (but not sulforaphane) modestly suppressed mouse splenocyte proliferation following supplementation of BALB/c mice diets. This effect was especially prominent if corrected for the loss of supplement “recall” as observed in cultured T-cells. These results suggest the potential use of these select phytochemicals for treating autoimmune and transplant patients, and support our strategy of using select phytochemicals to treat genetically-defined pathologies, an approach that we believe is simple, healthy, and cost-effective.

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Multiple oxidative stress-response members of the Adapt78 family

Cited by 17 publications

References 32 publications

Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease

Chronic high levels of the RCAN1-1 protein may promote neurodegeneration and Alzheimer disease

Fish oil improves gene targets of Down syndrome in C57BL and BALB/c mice

Select phytochemicals suppress human T-lymphocytes and mouse splenocytes suggesting their use in autoimmunity and transplantation

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