RGD Reference Report - Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein.

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Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein.
Authors:	Ortega, Juliana F de Conti, Aline Tryndyak, Volodymyr Furtado, Kelly S Heidor, Renato Horst, Maria Aderuza Fernandes, Laura Helena Gasparini Tavares, Paulo Eduardo Latorre Martins Pogribna, Marta Shpyleva, Svitlana Beland, Frederick A Pogribny, Igor P Moreno, Fernando Salvador
Citation:	Ortega JF, etal., Oncotarget. 2016 Apr 26;7(17):24339-47. doi: 10.18632/oncotarget.8248.
RGD ID:	151667433
Pubmed:	PMID:27013579 (View Abstract at PubMed)
PMCID:	PMC5029705 (View Article at PubMed Central)
DOI:	DOI:10.18632/oncotarget.8248 (Journal Full-text)
Hepatocellular carcinoma (HCC), an aggressive and the fastest growing life-threatening cancer worldwide, is often diagnosed at intermediate or advanced stages of the disease, which substantially limits therapeutic approaches for its successful treatment. This indicates that the prevention of hepatocarcinogenesis is probably the most promising approach to reduce both the HCC incidence and cancer-related mortality. In previous studies, we demonstrated a potent chemopreventive effect of tributyrin, a butyric acid prodrug, on experimental hepatocarcinogenesis. The cancer-inhibitory effect of tributyrin was linked to the suppression of sustained cell proliferation and induction of apoptotic cell death driven by an activation of the p53 apoptotic signaling pathway. The goal of the present study was to investigate the underlying molecular mechanisms linked to tributyrin-mediated p53 activation. Using in vivo and in vitro models of liver cancer, we demonstrate that an increase in the level of p53 protein in nuclei, a decrease in the level of cytoplasmic p53, and, consequently, an increase in the ratio of nuclear/cytoplasmic p53 in rat preneoplastic livers and in rat and human HCC cell lines caused by tributyrin or sodium butyrate treatments was associated with a marked increase in the level of nuclear chromosome region maintenance 1 (CRM1) protein. Mechanistically, the increase in the level of nuclear p53 protein was associated with a substantially reduced binding interaction between CRM1 and p53. The results demonstrate that the cancer-inhibitory activity of sodium butyrate and its derivatives on liver carcinogenesis may be attributed to retention of p53 and CRM1 proteins in the nucleus, an event that may trigger activation of p53-mediated apoptotic cell death in neoplastic cells.

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RGD Manual Disease Annotations Click to see Annotation Detail View

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
XPO1	Human	hepatocellular carcinoma	treatment	ISO	Xpo1 (Rattus norvegicus)		RGD
Xpo1	Rat	hepatocellular carcinoma	treatment	IDA			RGD
Xpo1	Mouse	hepatocellular carcinoma	treatment	ISO	Xpo1 (Rattus norvegicus)		RGD

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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Xpo1	Rat	cellular response to salt		IEP		sodium butyrate	RGD
Tp53	Rat	cellular response to triglyceride		IEP		tributyrin	RGD
Xpo1	Rat	cellular response to triglyceride		IEP		tributyrin	RGD

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Xpo1	Rat	DNA-binding transcription factor binding		IPI	Tp53 (Rattus norvegicus)		RGD
Tp53	Rat	transmembrane transporter binding		IPI	Xpo1 (Rattus norvegicus)		RGD

Objects Annotated

Genes (Rattus norvegicus)

Tp53 (tumor protein p53)

Xpo1 (exportin 1)

Genes (Mus musculus)

Xpo1 (exportin 1)

Genes (Homo sapiens)

XPO1 (exportin 1)

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InterViewer (Protein-Protein Interactions)	GViewer (Genome Viewer)	Variant Visualizer (Damaging Variants)

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Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein.