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- Table of Contents
Facts about CREB-regulated transcription coactivator 3.
Enhances the interaction of CREB1 with TAF4. Regulates the expression of specific CREB-activated genes such as the steroidogenic gene, StAR.
Human | |
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Gene Name: | CRTC3 |
Uniprot: | Q6UUV7 |
Entrez: | 64784 |
Belongs to: |
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TORC family |
CREB regulated transcription coactivator 3; CRTC3; FLJ21868; TORC3; TORC-3; TORC3CREB-regulated transcription coactivator 3; Transducer of CREB protein 3; transducer of regulated cAMP response element-binding protein (CREB) 3; Transducer of regulated cAMP response element-binding protein 3; transducer of regulated CREB protein 3
Mass (kDA):
66.959 kDA
Human | |
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Location: | 15q26.1 |
Sequence: | 15; NC_000015.10 (90529915..90645345) |
Predominantly expressed in B and T lymphocytes. Highest levels in lung. Also expressed in brain, colon, heart, kidney, ovary, and prostate. Weak expression in liver, pancreas, muscle, small intestine, spleen and stomach.
Nucleus. Cytoplasm. Appears to be mainly nuclear (PubMed:15454081). Translocates to the nucleus following adenylyl cyclase or MAP kinase activation (PubMed:30611118).
In order to detect CRTC3, researchers have developed antibodies against CRTC3. These antibodies are polyclonal or monoclonal and react with CRTC3 in various animal samples, including mouse and rabbit. This protein functions as a coactivator in the SIK/TORC signaling pathway and enhances interaction between CREB1 and TAF4, a transcription factor that regulates the expression of steroidogenic genes, including StAR.
The transcriptional coactivator CRTC3 is a component of the SIK/TORC signaling pathway that binds to CREB1. It acts independently of CREB1 phosphorylation and regulates several genes including steroidogenic gene StAR and PPARGC1A. Moreover, it induces mitochondrial biogenesis in muscle cells. It binds to CREB1 through its N-terminal region.
The CRTC3 sandwich enzyme immunoassay was designed to detect the protein in human tissue homogenates, cell lysates, and cell culture supernates. This assay is recommended for use in research laboratories where CRTC3 is detected by other biomarkers. The CRTC3 sandwich enzyme immunoassay is also applicable to other biological samples. Further functional studies are required to determine the role of CRTC3 in the cells.
CRTC3 was found to be a transcriptional coactivator with a similar pattern of activation to CRTC1. This protein also plays an important role in ACTH-mediated transcription. However, the expression pattern of CRTC3 and ACTH is not the same. Moreover, CRTC2 and CRTC3 were not affected by ACTH and CRTC3 were similar to basal levels after one hour.
Despite the negative feedback loops that maintain physiological balances, the depletion of CRTC3 in brown adipose tissue increases the body's cold tolerance. Despite this, the re-expression of miR-206 reversed the effects of CRTC3 depletion on cold tolerance. Similarly, small-molecule inhibitors of CRTC3 may provide therapeutic benefit for overweight individuals.
In addition, CRTC3 has been shown to inhibit mitochondrial biogenesis in response to mitochondria toxin. Therefore, siRNAs targeting this protein inhibit the induction of PGC-1a in response to rotenone. The siRNAs derived from the same cell line also showed that CRTC2 and CRTC3 bind to Pgc-1a. These results suggest that the CRTC3 protein regulates the production of mitochondrial proteins.
The CRTC3 gene is an important regulator of human chemokine IL-17. It is essential for the production of IL-17, a key mediator of apoptosis. By inhibiting CXCL1 expression, CRTC3 has the potential to prevent inflammation and improve the quality of human life. This gene is expressed in both the brown and white adipose tissues.
The CRTC2/3 gene is known to regulate CREB target genes. It inhibits CXCL1 and CXCL2 expression and blunts the activity of NFkB, a nuclear transcription factor. It is also possible that CRTCs act as primed promoters for NFkB recruitment. The CRTC2/NFkB co-bound peaks are enriched in AP1 binding sites, which are typically recognized by Jun/Fos. Moreover, CRTC1 is known to associate with AP1 and mediate induction of target gene expression. Future studies should reveal the mechanism through which CRTC1 is modulated by other nuclear factors.
Inhibition of CRTC activity can be achieved by siRNAs targeting SIK2 or CRTC. Inhibition of SIK2 or CRTC activity increased expression of the two inflammatory genes, CXCL1 and CXCL2. Inhibition of SIK2 or p65 did not alter the expression of MCP1.
The CRTC2/3 gene is important for insulin signaling and adipogenic genes. Loss of CXCL1 expression decreased circulating triglyceride and free fatty acid concentrations, and lipid accumulation was reduced in liver tissue of CXCL1 KO mice. This gene is known to play a role in cancer metastasis.
Inhibition of CXCL1 by anti-CRTC3 antibodies results in decreased body weight and adipose tissue fat. These mice have reduced levels of insulin in the blood and improved glucose tolerance. Furthermore, the immune-neutralized mice had lower levels of neutrophils and macrophages in the eWAT than wild-type mice.
CRTC3 knockout decreases adipocyte CXCL1 expression and enhances adipocyte insulin sensitivity. Inhibition of CXCL1 expression reverses the salutary effects of CRTC2/3 depletion. This is an important adipocyte protein that is involved in the regulation of glucose metabolism and insulin signaling.
The CRTC2/3 family of transcription factors influences the expression of CREB target genes, specifically CXCL1 and CXCL2. Interestingly, CRTC2/3 knockout mice exhibit reduced mRNA levels of these two chemokines in adipocytes. These reduced mRNA levels suggest that CRTC2/3 inhibit CXCL1/2 expression, which may contribute to the inhibition of neutrophil recruitment.
In a previous study, we found that CRTC3 reduced CXCL1 expression in differentiated white adipocytes. These mice were also able to improve their glucose tolerance by inhibiting CXCL1 expression. In addition, we found that CRTC3 reduced SIK2 protein expression and insulin signaling in eWAT-transformed mice. In addition, CRTC3 reduced CXCL1 expression and reduced lipid accumulation in adipocytes.
During HFD-induced fasting, mice lacking CRTC3 showed reduced circulating levels of CXCL1. This result was consistent with previous results showing that CRTC3 decreased the expression of CXCL1 in diabetic rats. Immuno-neutralized mice also had reduced neutrophil and macrophage infiltration into adipose tissue. Moreover, immunohistochemical analysis of eWAT tissue sections revealed lower levels of CXCL1/2 than mice with wild-type CXCL1.
CRTC2/3 were activated by HFD feeding, which promotes the expression of cytokine genes. These results indicate that HFD feeding may promote the expression of CRTC2/3 in stromal cells. The CRTC2/3 family inhibits STAT3 signaling, thereby reducing CXCL1 expression. These results suggest that CRTC3 regulates G-CSF expression.
CRTC3 reduces CXCL1, which inhibits triglyceride storage in the liver and BAT. In mice lacking CRTC3, the expression of these chemokines is reduced in both the BAT and liver. In addition, CXCL1 KO mice have decreased body weight and fat mass compared to WT littermates. This study suggests that the modulatory effects of CRTC3 in CXCL1 are developmental and not a consequence of inflammatory responses.
Inflammation is a major cause of type II diabetes, and increased adipose tissue mass triggers insulin resistance and pro-inflammatory cytokines. CREB and CRTC coactivators are implicated in the promotion of insulin resistance. Inflammatory cytokines can be inhibited by blocking the CRTC pathway, and sik2 is a regulator of SIK2 expression. The adipogenic factor C/EBPa regulates the expression of SIK2 and CRTCs. Therefore, it is believed that CRTC2/3 promote insulin resistance through the induced expression of CXCL1/2.
PMID: 14506290 by Iourgenko V., et al. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells.
PMID: 12693554 by Jikuya H., et al. Characterization of long cDNA clones from human adult spleen. II. The complete sequences of 81 cDNA clones.