J Vet Sci.  2013 Sep;14(3):257-262. 10.4142/jvs.2013.14.3.257.

Vitamin D3 up-regulated protein 1 controls the priming phase of liver regeneration

• Kwon HJ
• Hong SK
• Yoon WK
• Nam KH
• Choi IP
• Kim DY
• Kim HC
• Won YS

• KMID: 1705555
• DOI: http://doi.org/10.4142/jvs.2013.14.3.257

Abstract

Vitamin D3 up-regulated protein 1 (VDUP1) is a potent growth suppressor that inhibits tumor cell proliferation and cell cycle progression when overexpressed. In a previous study, we showed that VDUP1 knockout (KO) mice exhibited accelerated liver regeneration because such animals could effectively control the expression of cell cycle regulators that drive the G1-to-S phase progression. In the present study, we further investigated the role played by VDUP1 in initial priming of liver regeneration. To accomplish this, VDUP1 KO and wild-type (WT) mice were subjected to 70% partial hepatectomy (PH) and sacrificed at different times after surgery. The hepatic levels of TNF-alpha and IL-6 increased after PH, but there were no significant differences between VDUP1 KO and WT mice. Nuclear factor-kappaB (NF-kappaB), c-Jun-N-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT-3) were activated much earlier and to a greater extent in VDUP1 KO mice after PH. A single injection of TNF-alpha or IL-6 caused rapid activation of JNK and STAT-3 expression in both mice, but the responses were stronger and more sustained in VDUP1 KO mice. In conclusion, our findings provide evidence that VDUP1 plays a role in initiation of liver regeneration.

Keyword

c-Jun-N-terminal kinase; NF-kappaB; partial hepatectomy; signal transducer and activator of transcription 3; Vitamin D3 up-regulated protein 1

MeSH Terms

Animals
Blotting, Western
Carrier Proteins/*genetics/metabolism
Cell Proliferation
*Gene Expression Regulation
Hepatectomy
Hepatocytes/*cytology/physiology
JNK Mitogen-Activated Protein Kinases/genetics/metabolism
Liver/*physiology
Male
Mice, Knockout
NF-kappa B/genetics/metabolism
Polymerase Chain Reaction
*Regeneration
STAT3 Transcription Factor/genetics/metabolism
Thioredoxins/*genetics/metabolism
Carrier Proteins
JNK Mitogen-Activated Protein Kinases
NF-kappa B
STAT3 Transcription Factor
Thioredoxins

Figure

• 

  Fig. 1 Expression of genes encoding cytokines after partial hepatectomy (PH). The mRNA levels of hepatic tumor necrosis factor (TNF)-α (A) and interleukin (IL)-6 (B) were evaluated by real-time quantitative PCR, normalizing RNA relative to β-actin as the internal control. The values are the means ± SE (n = 3~4 for each group at each time point). VDUP1 KO: Vitamin D3 up-regulated protein 1 knockout.

• 

  Fig. 2 Activation of signaling pathways in regenerating liver after PH. Western blotting to detect expression of the nuclear factor-κB (NF-κB) p50 and p65 subunits (A), c-jun (B), and signal transducer and activator of transcription 3 (STAT-3) (C) in hepatic nuclear extracts. Densitometric changes are expressed as percentages of the WT values at 0 h. Values are the means ± SE (n = 3~4 for each group at each time point). *p < 0.05 vs. WT mice at the respective time points.

• 

  Fig. 3 The effects of TNF-α or IL-6 on c-Jun-N-terminal kinase and STAT-3 activation. Expression levels of c-jun (A) and STAT-3 (B). Nuclear proteins were extracted at the indicated times after TNF-α or IL-6 treatment, gel-separated, and immunoblotted using the indicated antibodies. Densitometric changes are expressed as percentages of the WT value at 0 h. Values are the means ± SE (n = 3~4 for each group at each time point). *p < 0.05 vs. the WT mice at the respective time points.

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