RACK1 and stratifin target ΔNp63α for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage

Alexey Fomenkov, Rachel Zangen, Yi Ping Huang, Motonobu Osada, Zhongmin Guo, Tanya Fomenkov, Barry Trink, David Sidransky, Edward A. Ratovitski

Research output: Contribution to journalArticle

Abstract

p53 family members with a transactivation (TA) domain induce cell cycle arrest and promote apoptosis. However, ΔNp63 isotypes lacking the TA-domain promote cell proliferation and tumorigenesis in vitro and in vyvo. Although p53, TAp63 or TAp73 are stabilized upon DNA damage, we found that the genotoxic stress agents induced a dramatic decrease and phosphorylation of ΔNp63α in squamous cell carcinoma cells. Further work revealed that RACK1 physically associated with the p63α C-terminal domain through its WD40 domain. However, stratifin binds with phosphorylated ΔNp63α in response to cisplatin. Upon DNA damage induced by cisplatin, stratifin mediated a nuclear export of ΔNp63α into cytoplasm and then RACK1 targeted latter into a proteasome degradation pathway possibly serving as an E3 ubiquitin ligase. Moreover, siRNA knockdown of both stratifin and RACK1 inhibited a nuclear export and protein degradation of ΔNp63α, respectively. Our data suggest that modification and downregulation of ΔNp63α is one of the major determinants of the cellular response to DNA damage in human head and neck cancers.

Original languageEnglish (US)
Pages (from-to)1285-1295
Number of pages11
JournalCell Cycle
Volume3
Issue number10
DOIs
StatePublished - Oct 2004

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Keywords

  • Cisplatin
  • RACK1
  • Stratifin squamous cell carcinomas
  • p53
  • p63

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Fomenkov, A., Zangen, R., Huang, Y. P., Osada, M., Guo, Z., Fomenkov, T., Trink, B., Sidransky, D., & Ratovitski, E. A. (2004). RACK1 and stratifin target ΔNp63α for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage. Cell Cycle, 3(10), 1285-1295. https://doi.org/10.4161/cc.3.10.1155