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Elimination of C/EBPα through the ubiquitin-proteasome system promotes the development of liver cancer in mice
Guo-Li Wang, … , Milton Finegold, Nikolai A. Timchenko
Guo-Li Wang, … , Milton Finegold, Nikolai A. Timchenko
Published June 1, 2010
Citation Information: J Clin Invest. 2010;120(7):2549-2562. https://doi.org/10.1172/JCI41933.
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Research Article Oncology

Elimination of C/EBPα through the ubiquitin-proteasome system promotes the development of liver cancer in mice

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Abstract

Despite significant advancements in our understanding of cancer development, the molecular mechanisms that underlie the formation of liver cancer remain largely unknown. C/EBPα is a transcription factor that regulates liver quiescence. Phosphorylation of C/EBPα at serine 193 (S193-ph) is upregulated in older mice and is thought to contribute to age-associated liver dysfunction. Because development of liver tumors is associated with increasing age, we investigated the role of S193-ph in the development of liver cancer using knockin mice expressing a phospho-mimetic aspartic acid residue in place of serine at position 193 (S193D) of C/EBPα. The S193D isoform of C/EBPα was able to completely inhibit liver proliferation in vivo after partial hepatectomy. However, treatment of these mice with diethylnitrosamine/phenobarbital (DEN/PB), which induces formation of liver cancer, actually resulted in earlier development of liver tumors. DEN/PB treatment was associated with specific degradation of both the S193-ph and S193D isoforms of C/EBPα through activation of the ubiquitin-proteasome system (UPS). The mechanism of UPS-mediated elimination of C/EBPα during carcinogenesis involved elevated levels of gankyrin, a protein that was found to interact with the S193-ph isoform of C/EBPα and target it for UPS-mediated degradation. This study identifies a molecular mechanism that supports the development of liver cancer in older mice and potential therapeutic targets for the prevention of liver cancer.

Authors

Guo-Li Wang, Xiurong Shi, Simon Haefliger, Jingling Jin, Angela Major, Polina Iakova, Milton Finegold, Nikolai A. Timchenko

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Figure 5

Elevation of gankyrin triggers degradation of C/EBPα by UPS.

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Elevation of gankyrin triggers degradation of C/EBPα by UPS.
(A) Inhibit...
(A) Inhibition of proteasome blocks degradation of S193D C/EBPα in DEN-treated livers. Protein extracts of S193D untreated (Con), DEN-treated (for 25 weeks), and DEN-treated mice injected with MG132 were examined by Western blotting with Abs to C/EBPα and ubiquitin. Middle panel shows results of Western blotting of C/EBPα IP with antibodies to ubiquitin. Positions of C/EBPα isoforms and ubiquitinated conjugates are shown on the right. (B) Gankyrin preferentially interacts with S193D isoform of C/EBPα. GST-S193A and GST-S193D mutants were incubated with nuclear extracts isolated from livers of mice treated with DEN/PB for 25 weeks. (C) Expression of gankyrin is increased in livers of DEN/PB-treated mice. Upper image shows Western blotting with antibodies to C/EBPα and gankyrin. Middle image shows densitometric calculations of the levels of C/EBPα and gankyrin (gank). Bottom image shows levels of gankyrin mRNA determined by RT-PCR and calculated as a ratio to β-actin. Data shown are mean ± SD. (D) Gankyrin and cdk4 are associated with C/EBPα at early time points after DEN treatments. C/EBPα was IP from nuclear extracts and probed with antibodies to gankyrin and cdk4. (E) Expression of proteins that regulate activity of cdk4. Western blotting of nuclear extracts of DEN-treated mice was performed with antibodies shown on the right. (F) Gankyrin displaces p16 from cdk4 and activates cdk4. Cdk4 was IP from nuclear extracts and probed with Abs to gankyrin and to p16 (Western). The cdk4 IPs were examined in a kinase assay with WT C/EBPα and with S193A-C/EBPα as substrates (kinase assay).

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