CREB Coactivators CRTC2 and CRTC3 Modulate Bone Marrow Hematopoiesis
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ABSTRACT:
PROVIDER: PRJNA407926 | ENA |
REPOSITORIES: ENA
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Project description:Populations of circulating immune cells are maintained in equilibrium through signals that enhance the retention or egress of hematopoietic stem cells (HSCs) from bone marrow (BM). Prostaglandin E2 (PGE2) stimulates HSC renewal and engraftment, for example, via induction of the cAMP pathway. Triggering of PGE2 receptors increases HSC survival in part via the PKA-mediated induction of the CREB signaling pathway. PKA stimulates cellular gene expression by phosphorylating CREB at Ser133 and by promoting the dephosphorylation of the cAMP Responsive Transcriptional Coactivators (CRTCs). We show here that disruption of both CRTC2 and CRTC3 causes embryonic lethality, and that a single allele of either CRTC2 or CRTC3 is sufficient for viability. CRTC2 knockout mice that express one CRTC3 allele (CRTC2/3m mice) develop neutrophilia and splenomegaly in adulthood due to the up-regulation of Granulocyte-Colony Stimulating Factor (G-CSF); these effects are reversed following administration of neutralizing anti-G-CSF antiserum. Adoptive transfer of CRTC2/3m BM conferred the splenomegaly/neutrophilia phenotype on WT recipients. Indeed, targeted disruption of both CRTC2 and CRTC3 in stromal cells with a mesenchymal Prx1-Cre transgene also promoted this phenotype. Depletion of CRTC2/3 was found to decrease the expression of Suppressor of Cytokine Signaling 3 (SOCS3), leading to increases in STAT3 phosphorylation and to the induction of CEBPb, a key regulator of the G-CSF gene. As small molecule inhibition of JAK activity disrupted CEBPb induction and reduced G-CSF expression in CRTC2/3m stromal cells, our results demonstrate how cross-coupling between the CREB/CRTC and JAK/STAT pathways contributes to BM homeostasis.
2018-02-01 | GSE103999 | GEO
Project description: Not available
| S-EPMC5676928 | biostudies-literature
Project description:Triggering of cAMP and mitogen-activated (MAPK) pathways in response to hormonal and growth factor cues promotes melanocyte pigmentation and survival in part through induction of the master regulator MITF by cAMP-responsive factor CREB. We examined the role of CREB coactivators (CRTC1-3) in transduction of cAMP and MAPK signals in melanocytes. We found that CRTC3 knock-out in mice and B16F1 melanoma cells decreases pigmentation by directly regulating the expression of the melanosomal transporter OCA2. In addition to effects of cAMP, CRTC3 activation was also promoted by ERK1/2-mediated phosphorylation at Ser391; amounts of phosphorylated CRTC3-S391 were constitutively elevated in human melanoma cells expressing mutated BRAF or NF1. Knock-out of CRTC3 in A375 melanoma cells impaired their anchorage-independent growth, migration and invasiveness, whereas CRTC3 over-expression increased survival in response to BRAF inhibition by vemurafenib. Analysis of spontaneous CRTC3 mutations in melanomas reveals that increased activity of this co-activator associates with reduced patient survival. Our results highlight the importance of CRTC3 in pigmentation and melanoma progression.
2022-04-12 | GSE154115 | GEO
Project description:Obesity stimulates the infiltration of adipose tissue by innate immune cells, which in turn promote insulin resistance via the NFkB mediated induction of pro-inflammatory cytokines, which interfere with triglyceride metabolism. The cAMP responsive factor CREB has also been implicated in adipose tissue inflammation and insulin resistance, although the underlying mechanism is unclear. Here, we show that high fat diet (HFD) feeding triggers activation of the CREB cofactors CRTC2 and CRTC3, which bind to CREB and mediate induction of CXCL1 and other cytokine genes in cooperation with NFkB. HFD feeding reduced adipocyte C/EBPa expression in adipose, leading to decreases in the expression of Salt Inducible Kinase 2 (SIK2), which otherwise phosphorylates and sequesters CRTCs in the cytoplasm. Depletion of SIK2 in adipose led to dephosphorylation of CRTC2 and CRTC3 (CRTC2/3) and to the induction of CXCL1 and other cytokine genes in adipocytes. Indeed, CRTC2/3 were found to stimulate the expression of a subset of cellular genes cooperatively with NF-kB in adipocytes. Knockout of both CRTC2 and CRTC3 in adipose decreased the expression of CXCL1/2 and thereby reduced neutrophil and macrophage infiltration. As depletion of CXCL1/2, with neutralizing antiserum or by KO of the CXCL1 gene restored glucose tolerance and insulin sensitivity in the setting of diet induced obesity, our results demonstrate that NF-kB and CREB/CRTC pathways modulate adipose tissue function in part via cooperative effects on target gene expression.
2021-10-27 | GSE160597 | GEO
Project description:Triggering of cAMP and mitogen-activated (MAPK) pathways in response to hormonal and growth factor cues promotes melanocyte pigmentation and survival in part through induction of the master regulator MITF by cAMP-responsive factor CREB. We examined the role of CREB coactivators (CRTC1-3) in transduction of cAMP and MAPK signals in melanocytes. We found that CRTC3 knock-out in mice and B16F1 melanoma cells decreases pigmentation by directly regulating the expression of the melanosomal transporter OCA2. In addition to effects of cAMP, CRTC3 activation was also promoted by ERK1/2-mediated phosphorylation at Ser391; amounts of phosphorylated CRTC3-S391 were constitutively elevated in human melanoma cells expressing mutated BRAF or NF1. Knock-out of CRTC3 in A375 melanoma cells impaired their anchorage-independent growth, migration and invasiveness, whereas CRTC3 over-expression increased survival in response to BRAF inhibition by vemurafenib. Analysis of spontaneous CRTC3 mutations in melanomas reveals that increased activity of this co-activator associates with reduced patient survival. Our results highlight the importance of CRTC3 in pigmentation and melanoma progression.
2022-04-12 | GSE154114 | GEO
Project description:Triggering of cAMP and mitogen-activated (MAPK) pathways in response to hormonal and growth factor cues promotes melanocyte pigmentation and survival in part through induction of the master regulator MITF by cAMP-responsive factor CREB. We examined the role of CREB coactivators (CRTC1-3) in transduction of cAMP and MAPK signals in melanocytes. We found that CRTC3 knock-out in mice and B16F1 melanoma cells decreases pigmentation by directly regulating the expression of the melanosomal transporter OCA2. In addition to effects of cAMP, CRTC3 activation was also promoted by ERK1/2-mediated phosphorylation at Ser391; amounts of phosphorylated CRTC3-S391 were constitutively elevated in human melanoma cells expressing mutated BRAF or NF1. Knock-out of CRTC3 in A375 melanoma cells impaired their anchorage-independent growth, migration and invasiveness, whereas CRTC3 over-expression increased survival in response to BRAF inhibition by vemurafenib. Analysis of spontaneous CRTC3 mutations in melanomas reveals that increased activity of this co-activator associates with reduced patient survival. Our results highlight the importance of CRTC3 in pigmentation and melanoma progression.
2022-04-12 | GSE154116 | GEO
Project description:Triggering of cAMP and mitogen-activated (MAPK) pathways in response to hormonal and growth factor cues promotes melanocyte pigmentation and survival in part through induction of the master regulator MITF by cAMP-responsive factor CREB. We examined the role of CREB coactivators (CRTC1-3) in transduction of cAMP and MAPK signals in melanocytes. We found that CRTC3 knock-out in mice and B16F1 melanoma cells decreases pigmentation by directly regulating the expression of the melanosomal transporter OCA2. In addition to effects of cAMP, CRTC3 activation was also promoted by ERK1/2-mediated phosphorylation at Ser391; amounts of phosphorylated CRTC3-S391 were constitutively elevated in human melanoma cells expressing mutated BRAF or NF1. Knock-out of CRTC3 in A375 melanoma cells impaired their anchorage-independent growth, migration and invasiveness, whereas CRTC3 over-expression increased survival in response to BRAF inhibition by vemurafenib. Analysis of spontaneous CRTC3 mutations in melanomas reveals that increased activity of this co-activator associates with reduced patient survival. Our results highlight the importance of CRTC3 in pigmentation and melanoma progression.
2022-04-12 | GSE154113 | GEO
Project description:CREB and CRTC2 ChIPseq analysis in LKB1-deficient and LKB1-reconstituted A549 NSCLC cells
2019-07-26 | GSE128871 | GEO
Project description:CRTC3 is CREB regulated transcriptional co-activators and prominently expressed in astrocyte cells. CRTC3 plays a specific role in determining the social heirarchical ranking in mice by confirming social rank test in CRTC3 KO mice. Loss of CRTC3 in astrocyte induced neuronal change and caused exchanging protein expression pattern. We used microarrays to determine the astrocyte-derived factors that were regulated by CRTC3 and related with social dominance behaviours of CRTC3 KO mice. We identifed distinct factor of down-regulated gene during primary astrocyte cell in CRTC3 KO.
2023-09-17 | GSE222741 | GEO
Project description:CRTC2 is a critical transcription cofactor that induces the glucose homeostatic genes by activating CREB. However, energy homeostasis is maintained by multiple pathways, therefore, it is possible that CRTC2 may interact with other transcription factors, especially under metabolic stress. Thereby, CRTC2 liver-specific knockout mice were created and the global proteome, phosphoproteome and acetylome from liver tissue under the high fat diet conditions were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. As expected, differentially expressed proteins (DEPs) are enriched in metabolic pathways that were subsequently corroborated by animal experiments. The consensus DEPs from these datasets were used as seed proteins to generate a protein-protein interaction (PPI) network using STRING and GeneMANIA identified fatty acid synthase (FASN) as the mutually relevant protein. Additional local-PPI (LPPI) analysis of CRTC2 and FASN with DEPs, SREBF1 was found to be a common mediator. CRTC2/CREB and SREBF1 are transcription factors, DNA-binding motif analysis showed multiple CRTC2/CREB regulated genes also possess SREBF1 binding motifs that unveil the possible induction by CRTC2/SREBF1 complex, which is reinforced by structural analysis. Thus, CRTC2/SREBF1 complex plausibly modulate the transcription of multiple proteins that fine-tune the cellular metabolism under metabolic stress.
2023-10-24 | PXD039817 | Pride