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CRTC3 is a coincidence detector for cAMP and growth factor signals in melanocytes and melanoma.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE154117 | GEO | 2022/04/12

REPOSITORIES: GEO

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CRTC3 is a coincidence detector for cAMP and growth factor signals in melanocytes and melanoma.

Project description:CRTC3 is a coincidence detector for cAMP and growth factor signals in melanocytes and melanoma.

| PRJNA645147 | ENA

TNFα-signal and cAMP-mediated signals oppositely regulate melanoma- associated ganglioside GD3 synthase gene in human melanocytes.

Project description:Analyses of expression and regulation of ganglioside synthases in melanocytes are important to understand roles of gangliosides in melanomagenesis. In this study, we analyzed the expression and regulatory mechanisms of glycosyltransferase genes responsible for ganglioside synthesis in normal melanocytes. We reported previously that culture supernatants of UVB-irradiated keratinocytes induced upregulation of ganglioside GD3 synthase gene in melanocytes, and mainly TNFα was responsible for it. Then, we found that elimination of dibutyryl cyclic AMP and IBMX from the medium also resulted in upregulation of the GD3 synthase gene. The addition of α-melanocyte-stimulating hormone which increases cAMP, to the medium led to a significant reduction in the GD3 synthase gene expression level, and a PKA inhibitor enhanced the GD3 synthase gene level. These results suggest that signals mediated via TNFα and cAMP oppositely regulate GD3 synthase gene expression in melanocytes. The results of an IKK inhibitor indicate the possibility that TNFα induces GD3 synthase gene expression via NF-κB signaling in melanocytes. When melanoma cells were treated by these factors, no fluctuation in the GD3 synthase gene expression level was observed, although an IKK inhibitor significantly suppressed it, suggesting that ganglioside synthase genes are regulated in distinct manners between melanocytes and melanomas.

| S-EPMC6791844 | biostudies-literature

Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines.

Project description:The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metastatic malignant melanoma of known PIK3CA, PTEN, NRAS and BRAF mutational status.Western blotting was used to compare the phosphorylation status of components of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways, as indices of pathway utilisation.Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways.Utilisation of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways in melanoma, as determined by phosphorylation of signalling components, varies widely across a series of cell lines, and does not directly reflect mutation of genes coding these components. The main difference between cultured normal melanocytes and melanoma cells is not the pathway utilisation itself, but rather in the serum dependence of pathway utilisation.

| S-EPMC3352269 | biostudies-literature

cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis.

Project description:In response to cold exposure, placental mammals maintain body temperature by increasing sympathetic nerve activity in brown adipose tissue (BAT). Triggering of β-adrenergic receptors on brown adipocytes stimulates thermogenesis via induction of the cAMP/PKA pathway. Although cAMP response element-binding protein (CREB) and its coactivators-the cAMP-regulated transcriptional coactivators (CRTCs)-mediate transcriptional effects of cAMP in most tissues, other transcription factors such as ATF2 appear critical for induction of thermogenic genes by cAMP in BAT. Brown adipocytes arise from Myf5-positive mesenchymal cells under the control of PRDM16, a coactivator that concurrently represses differentiation along the skeletal muscle lineage. Here, we show that the CREB coactivator CRTC3 is part of an inhibitory feedback pathway that antagonizes PRDM16-dependent differentiation. Mice with a knockout of CRTC3 in BAT (BKO) have increased cold tolerance and reduced adiposity, whereas mice overexpressing constitutively active CRTC3 in adipose tissue are more cold sensitive and have greater fat mass. CRTC3 reduced sympathetic nerve activity in BAT by up-regulating the expression of miR-206, a microRNA that promotes differentiation along the myogenic lineage and that we show here decreases the expression of VEGFA and neurotrophins critical for BAT innervation and vascularization. Sympathetic nerve activity to BAT was enhanced in BKO mice, leading to increases in catecholamine signaling that stimulated energy expenditure. As reexpression of miR-206 in BAT from BKO mice reversed the salutary effects of CRTC3 depletion on cold tolerance, our studies suggest that small-molecule inhibitors against this coactivator may provide therapeutic benefit to overweight individuals.

| S-EPMC6003335 | biostudies-literature

Melan-a melanocytes and B16 melanoma cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2008-07-31 | GSE11588 | GEO

Primary uveal melanoma cells, normal uveal melanocytes, neural crest stem cells, embryonic stem cells and uveal melanoma cell lines

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-02-14 | E-GEOD-44299 | biostudies-arrayexpress

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-04-29 | E-GEOD-54059 | biostudies-arrayexpress

Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment.

Project description:The second messenger 3',5'-cyclic adenosine monophosphate (cAMP) stimulates gene expression via the cAMP-regulated transcriptional coactivator (CRTC) family of cAMP response element-binding protein coactivators. In the basal state, CRTCs are phosphorylated by salt-inducible kinases (SIKs) and sequestered in the cytoplasm by 14-3-3 proteins. cAMP signaling inhibits the SIKs, leading to CRTC dephosphorylation and nuclear translocation. Here we show that although all CRTCs are regulated by SIKs, their interactions with Ser/Thr-specific protein phosphatases are distinct. CRTC1 and CRTC2 associate selectively with the calcium-dependent phosphatase calcineurin, whereas CRTC3 interacts with B55 PP2A holoenzymes via a conserved PP2A-binding region (amino acids 380-401). CRTC3-PP2A complex formation was induced by phosphorylation of CRTC3 at S391, facilitating the subsequent activation of CRTC3 by dephosphorylation at 14-3-3 binding sites. As stimulation of mitogenic pathways promoted S391 phosphorylation via the activation of ERKs and CDKs, our results demonstrate how a ubiquitous phosphatase enables cross talk between growth factor and cAMP signaling pathways at the level of a transcriptional coactivator.

| S-EPMC6317279 | biostudies-literature

Transcriptional Profile and Chromatin Accessibility in Zebrafish Melanocytes and Melanoma Tumors

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-05-24 | GSE178803 | GEO

Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate iPSC reprogramming of lineage-committed myeloid progenitors

Project description:This SuperSeries is composed of the SubSeries listed below.

2012-08-09 | GSE35029 | GEO