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TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria

Olav Gressner1, Tobias Schilling, Katja Lorenz

  • 1Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany.

The EMBO Journal
|June 10, 2005
PubMed

Insights

The tumor protein 63 (TP63) alpha isoform induces apoptosis by upregulating death receptors and mitochondrial pathways. This TAp63alpha function is crucial for chemotherapy effectiveness, as its inhibition leads to chemoresistance.

Area of Science:

  • Molecular Biology
  • Cell Death Pathways
  • Cancer Biology

Background:

  • TP63 is a key epithelial developmental gene homologous to p53.
  • TP63 produces two functional variants: TAp63 (transcriptionally active) and DeltaNp63 (dominant-negative).
  • The distinct roles of TAp63 isoforms in apoptosis and cancer therapy remain incompletely understood.

Purpose of the Study:

  • To elucidate the downstream molecular mechanisms by which TAp63alpha induces apoptosis.
  • To investigate the role of TAp63alpha in regulating death receptor pathways and mitochondrial apoptosis.
  • To determine the clinical relevance of TAp63alpha in chemotherapy sensitivity.

Main Methods:

  • Investigated TAp63alpha's direct transactivation of the CD95 gene.
  • Utilized stimulation and blocking experiments on CD95, TNF-R, and TRAIL-R death receptor systems.
  • Analyzed TAp63alpha's effect on proapoptotic Bcl-2 family members and mitochondrial apoptosis regulators.

Main Results:

  • TAp63alpha directly upregulates the CD95 death receptor via its promoter.
  • TAp63alpha activates expression of multiple death receptors (CD95, TNF-R, TRAIL-R) and mitochondrial apoptosis factors (Bax, BCL2L11, RAD9, DAP3, APAF1).
  • TAp63alpha is induced by chemotherapeutic drugs, and its inhibition confers chemoresistance.

Conclusions:

  • TAp63alpha plays a significant role in inducing apoptosis through both death receptor and mitochondrial pathways.
  • TAp63alpha is a critical mediator of chemosensitivity.
  • Targeting TAp63alpha may offer novel strategies for overcoming chemoresistance in cancer treatment.

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