Up-regulation of NFkappaB-responsive gene expression by DeltaNp73alpha in p53 null cells

Yasuharu Tanaka1, Katsuya Ota, Masanori Kameoka

  • 1Department of Biochemistry, Nara Medical University, Shijo-Cho 840, Kashihara, Nara 634-8521, Japan. ytanaka@naramed-u.ac.jp

Insights

Truncated p73 (DeltaNp73) activates NF-kappaB signaling independently of p53. This activation requires the proline-rich domain and C-terminus, demonstrating a novel role for DeltaNp73 in gene regulation.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Signal Transduction

Background:

  • The p73 protein is a tumor suppressor and a homolog of p53.
  • Truncated isoforms of p73, such as DeltaNp73, can interfere with p53 functions.
  • The role of DeltaNp73 in gene regulation independent of p53 is not fully understood.

Purpose of the Study:

  • To investigate whether DeltaNp73 can regulate gene expression in a p53-independent manner.
  • To identify the functional domains of p73 required for DeltaNp73-mediated gene regulation.
  • To elucidate the signaling pathways activated by DeltaNp73.

Main Methods:

  • Co-transfection of p53-null cell lines with DeltaNp73alpha and luciferase reporter plasmids.
  • Deletion analysis of p73 domains (TAD, PRD, C-terminus).
  • Assays for NF-kappaB activation, nuclear translocation, and endogenous gene expression (Bcl-XL).

Main Results:

  • DeltaNp73alpha selectively up-regulated NF-kappaB-responsive gene expression.
  • The transactivation domain (TAD)-truncated p73alpha required the proline-rich domain (PRD) and C-terminus for activity.
  • DeltaNp73alpha promoted NF-kappaB nuclear translocation and increased Bcl-XL expression.
  • p53 overexpression suppressed DeltaNp73alpha-mediated activation, and NF-kappaB inhibitors reduced this effect.

Conclusions:

  • TAD-truncated p73 (DeltaNp73alpha) activates NF-kappaB signaling independently of p53.
  • Both the PRD and C-terminus of p73 are crucial for DeltaNp73alpha-mediated NF-kappaB activation.
  • DeltaNp73alpha acts as an activator of the NF-kappaB pathway, influencing both reporter and endogenous gene expression.

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