ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria

André Schuster, Tobias Schilling, Vincenzo De Laurenzi, Andreas F. Koch, Sarah Seitz, Frank Staib, Andreas Teufel, Snorri S. Thorgeirsson, Peter R. Galle, Gerry Melino, Wolfgang Stremmel, Peter H. Krammer, Martina Müller

Research output: Contribution to journalArticle

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Abstract

Background and Aims: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 in HCC. results: ΔNp73β can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of proapoptotic target genes. Interference of ΔNp73β with apoptosis-/chemosensitivity takes place at several levels of apoptosis signaling. ΔNp73β negatively regulates the genes encoding for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, ΔNp73β represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, ΔNp73β inhibits apoptosis emanating from mitochondria. Conclusions: Thus, ΔNp73 expression in HCC selects against both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data suggest that ΔNp73 isoforms repress apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. The clinical importance of these data is evidenced by our finding that the ΔNp73β target gene signature can predict the prognosis of patients suffering from HCC.

Original languageEnglish
Pages (from-to)2629-2639
Number of pages11
JournalCell Cycle
Volume9
Issue number13
DOIs
Publication statusPublished - Jul 1 2010

Fingerprint

Death Domain Receptors
Hepatocellular Carcinoma
Mitochondria
Apoptosis
Protein Isoforms
Transcriptional Activation
Genes
Caspase 2
Caspase 3
Cell Cycle
Transcription Factors
Up-Regulation
Survival

Keywords

  • Apoptosis
  • Dominant negative p73
  • Hepatocellular carcinoma
  • p53 family
  • Therapy response

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Schuster, A., Schilling, T., De Laurenzi, V., Koch, A. F., Seitz, S., Staib, F., ... Müller, M. (2010). ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria. Cell Cycle, 9(13), 2629-2639. https://doi.org/10.4161/cc.9.13.12110

ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria. / Schuster, André; Schilling, Tobias; De Laurenzi, Vincenzo; Koch, Andreas F.; Seitz, Sarah; Staib, Frank; Teufel, Andreas; Thorgeirsson, Snorri S.; Galle, Peter R.; Melino, Gerry; Stremmel, Wolfgang; Krammer, Peter H.; Müller, Martina.

In: Cell Cycle, Vol. 9, No. 13, 01.07.2010, p. 2629-2639.

Research output: Contribution to journalArticle

Schuster, A, Schilling, T, De Laurenzi, V, Koch, AF, Seitz, S, Staib, F, Teufel, A, Thorgeirsson, SS, Galle, PR, Melino, G, Stremmel, W, Krammer, PH & Müller, M 2010, 'ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria', Cell Cycle, vol. 9, no. 13, pp. 2629-2639. https://doi.org/10.4161/cc.9.13.12110
Schuster, André ; Schilling, Tobias ; De Laurenzi, Vincenzo ; Koch, Andreas F. ; Seitz, Sarah ; Staib, Frank ; Teufel, Andreas ; Thorgeirsson, Snorri S. ; Galle, Peter R. ; Melino, Gerry ; Stremmel, Wolfgang ; Krammer, Peter H. ; Müller, Martina. / ΔNp73β is oncogenic in hepatocellular carcinoma by blocking apoptosis signaling via death receptors and mitochondria. In: Cell Cycle. 2010 ; Vol. 9, No. 13. pp. 2629-2639.
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abstract = "Background and Aims: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 in HCC. results: ΔNp73β can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of proapoptotic target genes. Interference of ΔNp73β with apoptosis-/chemosensitivity takes place at several levels of apoptosis signaling. ΔNp73β negatively regulates the genes encoding for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, ΔNp73β represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, ΔNp73β inhibits apoptosis emanating from mitochondria. Conclusions: Thus, ΔNp73 expression in HCC selects against both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data suggest that ΔNp73 isoforms repress apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. The clinical importance of these data is evidenced by our finding that the ΔNp73β target gene signature can predict the prognosis of patients suffering from HCC.",
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AU - Seitz, Sarah

AU - Staib, Frank

AU - Teufel, Andreas

AU - Thorgeirsson, Snorri S.

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AB - Background and Aims: p73 belongs to the p53 family of transcription factors known to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that drive the expression of two major p73 isoform subfamilies: TA and ΔN. In general, TAp73 isoforms show proapoptotic activities, whereas members of the N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain show antiapoptotic functions. We found that upregulation of ΔNp73 in hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 in HCC. results: ΔNp73β can directly interfere with the transcriptional activation function of the TA (containing the transactivation domain) isoforms of the p53 family and consequently inhibit transactivation of proapoptotic target genes. Interference of ΔNp73β with apoptosis-/chemosensitivity takes place at several levels of apoptosis signaling. ΔNp73β negatively regulates the genes encoding for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, ΔNp73β represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, ΔNp73β inhibits apoptosis emanating from mitochondria. Conclusions: Thus, ΔNp73 expression in HCC selects against both the death receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data suggest that ΔNp73 isoforms repress apoptosis-related genes of the extrinsic and intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. The clinical importance of these data is evidenced by our finding that the ΔNp73β target gene signature can predict the prognosis of patients suffering from HCC.

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