p63 Mediates Survival in Squamous Cell Carcinoma by Suppression of p73-dependent Apoptosis

Cancer Cell. 2006 Jan;9(1):45-56. doi: 10.1016/j.ccr.2005.12.013.

Abstract

We demonstrate that deltaNp63alpha is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress p73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress deltaNp63alpha. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of p73. Inhibition of p73-dependent transcription by deltaNp63alpha involves both direct promoter binding and physical interaction with p73. In HNSCC cells lacking endogenous deltaNp63alpha expression, bcl-2 is instead upregulated and can suppress p73-mediated death. Together, these data define a pathway whereby deltaNp63alpha promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Survival*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Genes, Tumor Suppressor / physiology*
  • Genes, bcl-2
  • Genes, p53
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / physiology*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / physiology*
  • Transcription Factors
  • Transcriptional Activation
  • Tumor Protein p73
  • Tumor Suppressor Proteins

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • PMAIP1 protein, human
  • Phosphoproteins
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Protein p73
  • Tumor Suppressor Proteins
  • p73 protein, human