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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 and Edward A. Ratovitski

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P53 family members with a transactivation domain induce cell cycle arrest and promote apoptosis. However, ΔNp63 isotypes lacking the transactivation (TA)- domain promote cell proliferation and tumorigenesis in vitro and in vivo. 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 down regulation of ΔNp63α is one of the major determinants of the cellular response to DNA damage in human head and neck cancers.

Authors

Alexey Fomenkov

Rachel Zangen

Yi-Ping Huang

Motonobu Osada

Zhongmin Guo

Tanya Fomenkov

Barry Trink

David Sidransky

Edward A. Ratovitski

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.