TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma

Martina Müller, T. Schilling, A. E. Sayan, A. Kairat, K. Lorenz, H. Schulze-Bergkamen, M. Oren, A. Koch, A. Tannapfel, W. Stremmel, G. Melino, P. H. Krammer

Research output: Contribution to journalArticle

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Abstract

We investigated the mechanisms by which TAp73β and dominant-negative p73 (ΔNp73) regulate apoptosis. TAp73β transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73β induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, ΔNp73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which ΔNp73 functionally inactivated the tumor suppressor action of p53 and TAp73β. Concomitantly, ΔNp73 inhibited apoptosis emanating from mitochondria. Thus, ΔNp73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73β. The importance of these data is evidenced by our finding that upregulation of ΔNp73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that ΔNp73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.

Original languageEnglish
Pages (from-to)1564-1577
Number of pages14
JournalCell Death and Differentiation
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2005

Fingerprint

Hepatocellular Carcinoma
Apoptosis
Death Domain Receptors
p53 Genes
Introns
Transcriptional Activation
Genes
DNA Damage
Neoplasms
Mitochondria
Up-Regulation
Binding Sites
Drug Therapy
Survival
Pharmaceutical Preparations

Keywords

  • Apoptosis
  • CD95
  • Chemosensitivity
  • Dominant-negative p73
  • Hepatocellular carcinoma
  • TAp73

ASJC Scopus subject areas

  • Cell Biology

Cite this

Müller, M., Schilling, T., Sayan, A. E., Kairat, A., Lorenz, K., Schulze-Bergkamen, H., ... Krammer, P. H. (2005). TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma. Cell Death and Differentiation, 12(12), 1564-1577. https://doi.org/10.1038/sj.cdd.4401774

TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma. / Müller, Martina; Schilling, T.; Sayan, A. E.; Kairat, A.; Lorenz, K.; Schulze-Bergkamen, H.; Oren, M.; Koch, A.; Tannapfel, A.; Stremmel, W.; Melino, G.; Krammer, P. H.

In: Cell Death and Differentiation, Vol. 12, No. 12, 12.2005, p. 1564-1577.

Research output: Contribution to journalArticle

Müller, M, Schilling, T, Sayan, AE, Kairat, A, Lorenz, K, Schulze-Bergkamen, H, Oren, M, Koch, A, Tannapfel, A, Stremmel, W, Melino, G & Krammer, PH 2005, 'TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma', Cell Death and Differentiation, vol. 12, no. 12, pp. 1564-1577. https://doi.org/10.1038/sj.cdd.4401774
Müller, Martina ; Schilling, T. ; Sayan, A. E. ; Kairat, A. ; Lorenz, K. ; Schulze-Bergkamen, H. ; Oren, M. ; Koch, A. ; Tannapfel, A. ; Stremmel, W. ; Melino, G. ; Krammer, P. H. / TAp73/ΔNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma. In: Cell Death and Differentiation. 2005 ; Vol. 12, No. 12. pp. 1564-1577.
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abstract = "We investigated the mechanisms by which TAp73β and dominant-negative p73 (ΔNp73) regulate apoptosis. TAp73β transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73β induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, ΔNp73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which ΔNp73 functionally inactivated the tumor suppressor action of p53 and TAp73β. Concomitantly, ΔNp73 inhibited apoptosis emanating from mitochondria. Thus, ΔNp73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73β. The importance of these data is evidenced by our finding that upregulation of ΔNp73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that ΔNp73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.",
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