CREB is activated by ER stress and modulates the unfolded protein response by regulating the expression of IRE1α and PERK

Kikuchi, Daisuke; Tanimoto, Kousuke; Nakayama, Koh

doi:10.1016/j.bbrc.2015.11.113

Cited by 36 publications

(35 citation statements)

References 17 publications

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“…Intriguingly, both CREB activation and increased expression have been linked to glucose deprivation [21, 22], and we find a similar response in melanoma cells (Figure 4A). Importantly, while CREB is a strong activator of the MITF promoter [20], we find that glucose deprivation reduces MITF expression.…”

Section: Resultssupporting

confidence: 79%

Glucose availability controls ATF4-mediated MITF suppression to drive melanoma cell growth

et al. 2017

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It is well know that cancer cells have adopted an altered metabolism and that glucose is a major source of energy for these cells. In melanoma, enhanced glucose usage is favoured through the hyper-activated MAPK pathway, which suppresses OXPHOS and stimulates glycolysis. However, it has not been addressed how glucose availability impacts on melanoma specific signaling pathways that drive melanoma cell proliferation. Here we show that melanoma cells are dependent on high glucose levels for efficient growth. Thereby, glucose metabolism controls the expression of the melanoma fate transcription factor MITF, a master regulator of melanoma cell survival and proliferation, invasion and therapy resistance. Restriction of glucose availability to physiological concentrations induces the production of reactive oxygen species (ROS). Increased ROS levels lead to the up-regulation of AFT4, which in turn suppresses MITF expression by competing with CREB, an otherwise potent inducer of the MITF promoter. Our data give new insight into the complex regulation of MITF, a key regulator of melanoma biology, and support previous findings that link metabolic disorders such as hyperglycemia and diabetes with increased melanoma risk.

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Section: Resultssupporting

confidence: 79%

Glucose availability controls ATF4-mediated MITF suppression to drive melanoma cell growth

et al. 2017

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“…Our data showing reduced CREB activity/phospho‐CREB levels after the depletion of cGMP support the cGMP/PKG regulation of CREB in the retina. In addition to protein kinases, CREB has been shown to be regulated by other cellular events, including ER stress and calcium signaling/ER calcium signaling . Data from the present study showed reduced CREB activity after Ryr2 deletion, supporting the regulation of RyR2/ER calcium homeostasis on CREB.…”

Section: Discussionsupporting

confidence: 74%

Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling‐induced cone degeneration in cyclic nucleotide‐gated channel deficiency

Yang

Butler

et al. 2020

FASEB j.

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Abbreviations: ATF6, activating transcription factor 6; CaMKII, calmodulin-dependent protein kinase II; cAMP, cyclic adenosine monophosphate; CAR, cone arrestin; cGMP, cyclic guanosine monophosphate; CHOP, CCAAT-enhancer-binding protein homologous protein; CNG, cyclic nucleotide-gated; CREB, cyclic adenosine monophosphate response element-binding protein; ER, endoplasmic reticulum; eIF2α, eukaryotic translation initiation factor 2 alpha; GFAP, glial fibrillary acidic protein; HRGP, human red/green pigment; Iba1, ionized calcium-binding adaptor molecule 1; IP 3 R, inositol-1,4,5trisphosphate receptor; Ire1α, serine/threonine-protein kinase/endoribonuclease 1α; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; qRT-PCR, quantitative reverse transcription polymerase chain reaction; RetGC1, retinal guanylate cyclase 1; RyR2, ryanodine receptor 2; SERCA, sarco/endoplasmic reticulum Ca 2+ -ATPase; TUNEL, terminal deoxynucleotidyltransferase dUTP nick end-labeling; UPR, unfolded protein response. AbstractPhotoreceptor cyclic nucleotide-gated (CNG) channels regulate Ca 2+ influx in rod and cone photoreceptors. Mutations in cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. Mice lacking functional cone CNG channel show endoplasmic reticulum (ER) stress-associated cone degeneration. The elevated cyclic guanosine monophosphate (cGMP)/cGMPdependent protein kinase (PKG) signaling and upregulation of the ER Ca 2+ channel ryanodine receptor 2 (RyR2) have been implicated in cone degeneration. This work investigates the potential contribution of RyR2 to cGMP/PKG signaling-induced ER stress and cone degeneration. We demonstrated that the expression and activity of RyR2 were highly regulated by cGMP/PKG signaling. Depletion of cGMP by deleting retinal guanylate cyclase 1 or inhibition of PKG using chemical inhibitors suppressed the upregulation of RyR2 in CNG channel deficiency. Depletion of cGMP or deletion of Ryr2 equivalently inhibited unfolded protein response/ER stress, activation of the CCAAT-enhancer-binding protein homologous protein, and activation of the cyclic adenosine monophosphate response element-binding protein, leading to early-onset cone protection. In addition, treatment with cGMP significantly enhanced Ryr2 expression in cultured photoreceptor-derived Weri-Rb1 cells. Findings from this work demonstrate the regulation of cGMP/PKG signaling on RyR2 in the retina and support the role of RyR2 upregulation in cGMP/PKG signaling-induced ER stress and photoreceptor degeneration. K E Y W O R D S cGMP/PKG signaling, CNG channel, cone photoreceptors, retinal degeneration, ryanodine receptor 6336 | YANG et Al.

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“…Thapsigargin-increased cytosolic calcium levels can lead to the activation of PPP3/calcineurin, a phosphatase activating CRTC1. 28 Consistently ER stress has been shown to activate CREB1, 53 possibly through CRTC1 regulation, which requires further investigation. In addition, ER stress also induces production of cytokines including IL1B through activating ERN1/IRE1a.…”

Section: Discussionmentioning

confidence: 99%

Autophagy gene ATG7 regulates ultraviolet radiation-induced inflammation and skin tumorigenesis

et al. 2017

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Macroautophagy (hereafter autophagy) is a cellular "self-eating" process that is implicated in many human cancers, where it can act to either promote or suppress tumorigenesis. However, the role of autophagy in regulation of inflammation during tumorigenesis remains unclear. Here we show that autophagy is induced in the epidermis by ultraviolet (UV) irradiation and autophagy gene Atg7 promoted UV-induced inflammation and skin tumorigenesis. Atg7 regulated UV-induced cytokine expression and secretion, and promoted Ptgs2/Cox-2 expression through both a CREB1/CREB-dependent cell autonomous mechanism and an IL1B/IL1β-dependent non-cell autonomous mechanism. Adding PGE increased UV-induced skin inflammation and tumorigenesis, reversing the epidermal phenotype in mice with Atg7 deletion in keratinocytes. Similar to ATG7 knockdown in human keratinocytes, ATG5 knockdown inhibited UVB-induced expression of PTGS2 and cytokines. Furthermore, ATG7 loss increased the activation of the AMPK pathway and the phosphorylation of CRTC1, and led to endoplasmic reticulum (ER) accumulation and reduction of ER stress. Inducing ER stress and inhibiting calcium influx into the ER by thapsigargin reverses the inflammation and tumorigenesis phenotype in mice with epidermal Atg7 deletion. Taken together, these findings demonstrate that deleting autophagy gene Atg7 leads to a suppression of carcinogen-induced protumorigenic inflammatory microenvironment and tumorigenesis of the epithelium.

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CREB is activated by ER stress and modulates the unfolded protein response by regulating the expression of IRE1α and PERK

Cited by 36 publications

References 17 publications

Glucose availability controls ATF4-mediated MITF suppression to drive melanoma cell growth

Glucose availability controls ATF4-mediated MITF suppression to drive melanoma cell growth

Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling‐induced cone degeneration in cyclic nucleotide‐gated channel deficiency

Autophagy gene ATG7 regulates ultraviolet radiation-induced inflammation and skin tumorigenesis

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