Dataset Information

Keratin 23 Is a Peroxisome Proliferator-Activated Receptor Alpha-Dependent, MYC-Amplified Oncogene That Promotes Hepatocyte Proliferation.

ABSTRACT: Chronic activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes MYC-linked hepatocellular carcinoma (HCC) in mice. Recent studies have shown that MYC can function as an amplifier of transcription where MYC does not act as an "on-off" switch for gene expression but rather accelerates transcription rates at active promoters by stimulating transcript elongation. Considering the possibility that MYC may amplify the expression of PPARA target genes to potentiate cell proliferation and liver cancer, gene expression was analyzed from livers of wild-type and liver-specific Myc knockout (Myc?Hep ) mice treated with the PPARA agonist pirinixic acid. A subset of PPARA target genes was amplified in the presence of MYC, including keratin 23 (Krt23). The induction of Krt23 was significantly attenuated in Myc?Hep mice and completely abolished in Ppara-null mice. Reporter gene assays and chromatin immunoprecipitation confirmed direct binding of both PPARA and MYC to sites within the Krt23 promoter. Forced expression of KRT23 in primary hepatocytes induced cell cycle-related genes. These data indicate that PPARA activation elevates MYC expression, which in turn potentiates the expression of select PPARA target genes involved in cell proliferation. Finally, KRT23 protein is highly elevated in human HCCs. Conclusion: These results revealed that MYC-mediated transcriptional potentiation of select PPARA target genes, such as Krt23, may remove rate-limiting constraints on hepatocyte growth and proliferation leading to liver cancer.

SUBMITTER: Kim D

PROVIDER: S-EPMC6597269 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Peroxisome proliferator-activated receptor γ (PPARγ) has 2 protein isoforms (PPARγ1 and PPARγ2) generated by alternative promoter usage and alternative splicing. However, their functional uniqueness and similarity remain unclear. In the study, we investigated the effects of lentivirus-mediated overexpression of PPARγ1 and PPARγ2 on proliferation, apoptosis, and differentiation of the immortalized chicken preadipocytes. Cell Counting Kit-8 assay showed PPARγ1 and PPARγ2 overexpression markedly suppressed cell proliferation, and fluorescence activated cell sorting analysis showed that PPARγ1 and PPARγ2 overexpression caused cell cycle arrest at G0/G1 phase. Cell death detection ELISA analysis showed both PPARγ1 and PPARγ2 overexpression induced cell apoptosis. Oil red O staining and gene expression analysis showed both PPARγ1 and PPARγ2 overexpression promoted preadipocyte differentiation. In the presence of PPARγ ligand, rosiglitazone, PPARγ2 overexpression was more potent in inducing apoptosis, promoting adipogenesis, and suppressing cell proliferation than PPARγ1 overexpression. We further explored the molecular basis for their functional differences. Reporter gene assay showed that under ligand conditions, PPARγ2 overexpression resulted in 1.68-fold increase in transcription activity compared with PPARγ1. Electrophoretic mobility shift assay showed both PPARγ1 and PPARγ2 could bind to PPAR response element (PPRE) as heterodimer with retinoid X receptor alpha, and by comparison, PPARγ2 had a higher affinity for PPRE than PPARγ1. Reporter gene assay showed expression PPARγ1 and PPARγ2 similarly induced fatty acid synthase and adipocyte fatty acid-binding protein promoter activity but differentially induced lipoprotein lipase and perilipin 1 promoter activities. Coimmunoprecipitation analysis showed that PPARγ1 and PPARγ2 interacted similarly with the coactivators, Tat-interacting protein 60. Taken together, our results demonstrate that PPARγ1 and PPARγ2 differentially regulate preadipocyte proliferation, apoptosis, and differentiation as a result of their distinct and overlapping molecular functions.

Dataset Information

Keratin 23 Is a Peroxisome Proliferator-Activated Receptor Alpha-Dependent, MYC-Amplified Oncogene That Promotes Hepatocyte Proliferation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets