Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBPα growth inhibitory activity

Wang, Guoli; Iakova, Polina; Wilde, Margie; Awad, Samir S.; Timchenko, Nikolai A.

doi:10.1101/gad.1183304

Cited by 130 publications

(213 citation statements)

References 31 publications

(70 reference statements)

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“…Nuclear extracts were isolated from livers as described earlier (Timchenko et al ., 1997) and fractionated by size‐exclusion column SEC400 (HPLC, HR; Bio‐Rad Laboratories Inc, Hercules, CA USA). The detailed procedure for the analysis of C/EBPα complexes is described in our previous papers (Wang et al ., 2001, 2004). Briefly, gel filtration fractions were loaded on denaturing gradient (4‐20%) PAAG, blotted onto membrane, and probed with antibodies to C/EBPα (14AA), HDAC1, HP1α, and Brm (Santa Cruz Biotechnology, Dallas, Texas+9), to detect C/EBPα complexes, C/EBPα was immunoprecipitated from each fraction, and IPs were probed with antibodies to HDAC1.…”

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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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: 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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“…94 The apparent paradox of high levels of C/EBPα protein in some human liver tumors suggests that alterations in gene expression and/or signaling events in liver tumors may either inactivate or override the anti-proliferative function of C/EBPα. 95 In a recently published study, Wang and colleagues presented evidence implicating AKT/protein kinase B (PKB), an important mediator of insulin signaling in neutralizing the growth-inhibitory function of C/EBPα. 95 In this model, AKT/PKB activation of protein phosphatase 2A leads to the dephosphorylation of C/EBPα on Serine 193 and subsequent loss of cyclin dependent kinase inhibition by C/EBPα.…”

Section: Inhibitors Of Hepatocyte Proliferationmentioning

confidence: 99%

Cell cycle regulation and hepatocarcinogenesis

Greenbaum¹

2004

Cancer Biology & Therapy

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“…SET is an inhibitor of the PP2A, which regulates cell proliferation, survival, and differentiation. 25 The overexpression of I2PP2A in FTC versus FA and NT was confirmed by immunohistochemistry ( Figure 5B). …”

Section: Differential Protein Expression In Fa and Ftcmentioning

confidence: 72%

Dissecting Molecular Events in Thyroid Neoplasia Provides Evidence for Distinct Evolution of Follicular Thyroid Adenoma and Carcinoma

Krause¹,

Prawitt²,

Eszlinger³

et al. 2011

The American Journal of Pathology

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Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-␥ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, ␥-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC.

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Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBPα growth inhibitory activity

Cited by 130 publications

References 31 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

Cell cycle regulation and hepatocarcinogenesis

Dissecting Molecular Events in Thyroid Neoplasia Provides Evidence for Distinct Evolution of Follicular Thyroid Adenoma and Carcinoma

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