Growth Hormone Corrects Proliferation and Transcription of Phosphoenolpyruvate Carboxykinase in Livers of Old Mice via Elimination of CCAAT/Enhancer-binding Protein α-Brm Complex

Wang, Guo Li; Shi, Xiurong; Salisbury, Elizabeth; Sun, Yuxiang; Albrecht, Jeffrey H.; Smith, Roy G.; Timchenko, Nikolai A.

doi:10.1074/jbc.m608226200

Cited by 34 publications

(69 citation statements)

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“…This work focused on the C/EBPα pathway because our previous experiments showed that hepatic C/EBPα phosphorylation is increased by ghrelin (Wang et al ., 2007). Although the contribution of other pathways was not characterized here in detail, the fact that transcript and protein levels for mediators in these pathways were similar between groups suggests that they do not play a major role in mediating the effects of ghrelin deletion in this setting.…”

Section: Discussionmentioning

confidence: 99%

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Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

et al. 2017

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SummaryNonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. NAFLD usually begins as low‐grade hepatic steatosis which further progresses in an age‐dependent manner to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma in some patients. Ghrelin is a hormone known to promote adiposity in rodents and humans, but its potential role in hepatic steatosis is unknown. We hypothesized that genetic ghrelin deletion will protect against the development of age‐related hepatic steatosis. To examine this hypothesis, we utilized ghrelin knockout (KO) mice. Although no different in young animals (3 months old), we found that at 20 months of age, ghrelin KO mice have significantly reduced hepatic steatosis compared to aged‐matched wild‐type (WT) mice. Examination of molecular pathways by which deletion of ghrelin reduces steatosis showed that the increase in expression of diacylglycerol O‐acyltransferase‐1 (DGAT1), one of the key enzymes of triglyceride (TG) synthesis, seen with age in WT mice, is not present in KO mice. This was due to the lack of activation of CCAAT/enhancer binding protein‐alpha (C/EBPα) protein and subsequent reduction of C/EBPα‐p300 complexes. These complexes were abundant in livers of old WT mice and were bound to and activated the DGAT1 promoter. However, the C/EBPα‐p300 complexes were not detected on the DGAT1 promoter in livers of old KO mice resulting in lower levels of the enzyme. In conclusion, these studies demonstrate the mechanism by which ghrelin deletion prevents age‐associated hepatic steatosis and suggest that targeting this pathway may offer therapeutic benefit for NAFLD.

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Section: Discussionmentioning

confidence: 99%

“…ChIP assays were performed using ChIP It kit as described previously ( Jin et al ., 2009; Wang et al., 2007; Wang et al ., 2008b). Briefly, chromatin solutions were prepared from livers of young and old ghrelin wild‐type and ghrelin knockout mice.…”

Section: Methodsmentioning

confidence: 99%

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

et al. 2017

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“…Additionally, small-molecule inhibitors of CDK4 failed to alter cyclin D3-mediated AR suppression (data not shown). Together, these data indicate that unlike C/EBP regulation (Timchenko et al, 2006;Wang et al, 2006Wang et al, , 2007 cyclin D3 acts to block liganddependent AR activation independent of CDK4.…”

Section: Resultsmentioning

confidence: 78%

“…However, ectopic expression of CDK4/6 abrogated this activity, suggesting that CDK4 activation counterbalances the potentiating effects (Jian et al, 2005). Thus, while cyclin D3 depends upon CDK4-kinase activity to control C/EBPa in liver cells, it appears to impinge on VDR and AR independently of CDK4 function (Timchenko et al, 2006;Wang et al, 2006Wang et al, , 2007. It will be intriguing to determine whether these CDK4-independent effects are reliant on the newly identified role of cyclin D3 in CDK11 activation (Zong et al, 2007).…”

Section: Cyclin D3 Expression Is Altered In Pca Progressionmentioning

confidence: 99%

“…Therein, cyclin D3/ CDK4 phosphorylation of CUGBP1 controls C/EBPb translation, thus inhibiting hepatocyte proliferation in aged livers. Lastly, C/EBPa is a target of cyclin D3/ CDK4-mediated phosphorylation that stabilizes growth inhibitory C/EBPa-CDK2 or C/EBPa-Brm complexes (Timchenko et al, 2006;Wang et al, 2006Wang et al, , 2007. These observations represent a minority of non-overlapping functions elicited by D-cyclins, regardless of CDKkinase activity.…”

Section: Introductionmentioning

confidence: 99%

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Cyclin D3 action in androgen receptor regulation and prostate cancer

et al. 2007

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Prostate cancer (PCa) cell proliferation is dependent on activation of the androgen receptor (AR), a liganddependent transcription factor. AR activation controls G1-S phase progression through fostering enhanced translation of the D-type cyclins, which promote cell cycle progression through activation of CDK4/6. However, the D-type cyclins harbor additional, CDK4/6 kinase-independent, functions through manipulation of transcription factors, including AR. It was previously established that cyclins D1 and D3 have the potential to modulate AR, and with regard to cyclin D1, disruption of this function occurs in human tumors. Therefore, it was essential to interrogate cyclin D3 function in this tumor type. Here, we show that cyclin D3 is found in association with AR in PCa cells, as mediated through a conserved motif. Cyclin D3 functions to attenuate AR activity through defined mechanisms that include modulation of ligand-dependent conformational changes and modulation of chromatin binding activity. Accumulated cyclin D3 slows cell proliferation in AR-dependent cells, thus suggesting that androgen-induced D-type cyclin production serves to temper the mitogenic response to androgen. Supporting this hypothesis, it is shown that cyclin D3 expression is reduced in primary PCas as a function of tumor grade, and inversely correlates with the proliferative index. In total, these data identify cyclin D3 as a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in PCa.

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Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

et al. 2019

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Forkhead box transcription factor M1 ( FOXM 1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells ( DC s). Although previous work has shown that FOXM 1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM 1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM 1 in regulating bone marrow‐derived dendritic cell ( BMDC ) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM 1 retarded maturation phenotypes of BMDC s, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 ( IL ‐12) p70 in tumor‐bearing mice ( TBM ). Notably, FOXM 1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDC s. Increased H3K79me2 enrichment was observed at the FOXM 1 promoter in both BMDC s from TBM , and in BMDC s from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment ( TME ). Furthermore, inhibition of the H3K79 methyltransferase DOT 1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM 1 and partially reversed its immunosuppressive effects on BMDC s. Furthermore, we found that FOXM 1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDC s in vitro ; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM 1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM 1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDC s through the Wnt5a signaling pathway, and thus provide novel insights into FOXM 1‐based antitumor immunotherapy.

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Growth Hormone Corrects Proliferation and Transcription of Phosphoenolpyruvate Carboxykinase in Livers of Old Mice via Elimination of CCAAT/Enhancer-binding Protein α-Brm Complex

Cited by 34 publications

References 30 publications

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

Cyclin D3 action in androgen receptor regulation and prostate cancer

Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

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