Inhibition of c-Myc expression sensitizes hepatocytes to tumor necrosis factor-induced apoptosis and necrosis

Hailing Liu, Chau R. Lo, Brett E. Jones, Zehra Pradhan, Anu Srinivasan, Karen L. Valentino, Richard J. Stockert, Mark J. Czaja

Research output: Contribution to journalArticle

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Abstract

The typical proliferative response of hepatocytes to tumor necrosis factor (TNF) can be converted to a cytotoxic one by transcriptional arrest. Although NF-κB activation is critical for hepatocyte resistance to TNF toxicity, the contribution of other TNF-inducible transcription factors remains unknown. To determine the function of c-Myc in hepatocyte sensitivity to TNF, stable transfectants of the rat hepatocyte cell line RALA255-10G containing sense and antisense c-myc expression vectors were isolated with increased (S-Myc cells) and decreased (AN-Myc cells) c-Myc transcriptional activity. While S-Myc cells proliferated in response to TNF treatment, AN-Myc cells underwent 32% cell death within 6 h. Fluorescent microscopic studies indicated that TNF induced apoptosis and necrosis in AN-Myc cells. Cell death was associated with DNA hypoploidy and poly(ADP-ribose) polymerase cleavage but occurred in the absence of detectable caspase-3, -7, or -8 activation. TNF-induced, AN-Myc cell death was dependent on Fas-associated protein with death domain and partially blocked by caspase inhibitors. AN-Myc cells had decreased levels of NF-κB transcriptional activity, but S-Myc cells maintained resistance to TNF despite NF-κB inactivation, suggesting that c-Myc and NF-κB independently mediate TNF resistance. Thus, in the absence of sufficient c-Myc expression, hepatocytes are sensitized to TNF-induced apoptosis and necrosis. These findings demonstrate that hepatocyte resistance to TNF is regulated by multiple transcriptional activators.

Original languageEnglish (US)
Pages (from-to)40155-40162
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number51
DOIs
StatePublished - Dec 22 2000

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Hepatocytes
Necrosis
Tumor Necrosis Factor-alpha
Apoptosis
Cell death
Cell Death
Fas-Associated Death Domain Protein
Chemical activation
Caspase 7
Caspase Inhibitors
Poly(ADP-ribose) Polymerases
Caspase 3
Toxicity
Rats
Transcription Factors
Cells
Cell Line
DNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Liu, H., Lo, C. R., Jones, B. E., Pradhan, Z., Srinivasan, A., Valentino, K. L., ... Czaja, M. J. (2000). Inhibition of c-Myc expression sensitizes hepatocytes to tumor necrosis factor-induced apoptosis and necrosis. Journal of Biological Chemistry, 275(51), 40155-40162. https://doi.org/10.1074/jbc.M001565200

Inhibition of c-Myc expression sensitizes hepatocytes to tumor necrosis factor-induced apoptosis and necrosis. / Liu, Hailing; Lo, Chau R.; Jones, Brett E.; Pradhan, Zehra; Srinivasan, Anu; Valentino, Karen L.; Stockert, Richard J.; Czaja, Mark J.

In: Journal of Biological Chemistry, Vol. 275, No. 51, 22.12.2000, p. 40155-40162.

Research output: Contribution to journalArticle

Liu, H, Lo, CR, Jones, BE, Pradhan, Z, Srinivasan, A, Valentino, KL, Stockert, RJ & Czaja, MJ 2000, 'Inhibition of c-Myc expression sensitizes hepatocytes to tumor necrosis factor-induced apoptosis and necrosis', Journal of Biological Chemistry, vol. 275, no. 51, pp. 40155-40162. https://doi.org/10.1074/jbc.M001565200
Liu, Hailing ; Lo, Chau R. ; Jones, Brett E. ; Pradhan, Zehra ; Srinivasan, Anu ; Valentino, Karen L. ; Stockert, Richard J. ; Czaja, Mark J. / Inhibition of c-Myc expression sensitizes hepatocytes to tumor necrosis factor-induced apoptosis and necrosis. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 51. pp. 40155-40162.
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